Method and preparing fused oxazinones

ABSTRACT

A method for preparing a fused oxazinone is disclosed in which a carboxylic acid is contacted with a sulfonyl chloride and an isatoic anhydride in the presence of a tertiary amine, the nominal mole ratio of said sulfonyl chloride to said carboxylic acid being from about 1.0 to 1.5 and the nominal mole ratio of said isatoic anhydride to said carboxylic acid is from about 0.8 to 1.2. Also disclosed is a method for preparing a compound of Formula (III), using a compound of Formula (1a) that is characterized by preparing the fused oxazinone of Formula (1a) by the method above, using a compound of the formula LS(O) 2 Cl as the sulfonyl chloride, a compound of Formula (2′) as the carboxylic acid, and a compound of Formula (5′) as the isatoic anhydride wherein L, X, Y and R 1  through R 9  are as defined in the disclosure

BACKGROUND OF THE INVENTION

A need exists for additional methods for preparing fused oxazinones. Such compounds include intermediates for the preparation of crop protection agents, pharmaceuticals and other fine chemicals.

Fused oxazinones have been prepared by a variety of methods. For example, N-acylanthranilic acids have been treated with acetic anhydride, anthranilic acids have been treated with carboxylic acid anhydrides, and anthranilic acids and carboxylic acids have been coupled in the presence of various dehydrating agents (see G. M. Coppola, J. Heterocyclic Chemistry 1999, 36, 563-588). Fused oxazinones have also been prepared by treatment of ortho-amino carboxylic acids with carboxylic acid chlorides in the presence of base (see e.g., Jakobsen et al., Biorganic and Medicinal Chemistry 2000, 8, 2803-2812 and Jakobsen et al., Biorganic and Medicinal Chemistry 2000, 8, 2095-2103). Benzoxazinones have also been prepared by treatment of a carboxylic acid with a sulfonyl chloride and then treatment with an anthranilic acid (see D. V. Ramana and E. Kantharaj, Org. Prep. Proced. Int. 1993, 25, 588).

SUMMARY OF THE INVENTION

This invention provides a method for preparing a fused oxazinone. This method comprises:

contacting a carboxylic acid with a sulfonyl chloride and an isatoic anhydride in the presence of a tertiary amine to form the fused oxazinone, the nominal mole ratio of said sulfonyl chloride to said carboxylic acid being from about 1.0 to 1.5 and the nominal mole ratio of said isatoic anhydride to said carboxylic acid being from about 0.8 to 1.2.

This invention also relates to a method for preparing a compound of Formula III,

wherein

-   -   X is N or CR⁶;     -   Y is N or CH;     -   R¹ is H;     -   R² is H or CH₃;     -   R³ is C₁-C₆ alkyl;     -   R⁴ is C₁-C₄ alkyl or halogen;     -   R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, CN or halogen;     -   R⁶ and R⁷ are independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl,         halogen, CN or C₁-C₄ haloalkoxy;     -   R⁸ is H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆         cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl, C₂-C₄         haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂, C₁-C₄         alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,         C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆         cycloalkylamino, (C₁-C₄ alkyl)(C₃-C₆ cycloalkyl)amino, C₂-C₄         alkylcarbonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl,         C₃-C₈ dialkylaminocarbonyl or C₃-C₆ trialkylsilyl;     -   R⁹ is CF₃, OCF₃, OCHF₂, OCH₂CF₃, S(O)_(p)CF₃, S(O)_(p)CHF₂ or         halogen; and     -   p is 0, 1 or 2;         using a compound of Formula 1a

wherein the definitions of X, Y, R⁴, R⁵, R⁷, R⁸ and R⁹ are the same as for Formula III. This method is characterized by preparing the compound of Formula 1a (i.e. a subgenus of Formula 1 described below) by the method as indicated above. Formula 1a compounds may be prepared using a compound of the formula LS(O)₂Cl (wherein L is selected from alkyl, haloalkyl and phenyl optionally substituted with from one to three substituents independently selected from alkyl or halogen) as the sulfonyl chloride, a compound of Formula 2′ as the carboxylic acid, and a compound of Formula 5′ as the isatoic anhydride

wherein the definitions of X, Y, R⁴, R⁵, R⁷, R⁸ and R⁹ are the same as for Formula III.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of this invention involves the use of tertiary amines together with sulfonyl chloride compounds to provide advantageous production of fused oxazinones. The tertiary amine is used to facilitate contact of the carboxylic acid with the sulfonyl chloride compound and the isatoic anhydride. The sulfonyl chloride compound is used as a reactant to facilitate coupling of the carboxylic acid with the isatoic anhydride to form the fused oxazinone. The components of the reaction mixture can be combined in various orders, which allows for fewer and simpler operations as compared to previously known processes for the production of oxazinones such as 1. These aspects provide effective production of the fused oxazinone while limiting the amounts of the carboxylic acid, the sulfonyl chloride and the isatoic anhydride that are consumed during the formation of the fused oxazinone. This can be especially important when the carboxylic acid is valuable, complex and/or difficult to obtain, and can reduce production costs as compared to previously known processes by reducing consumption of raw materials and by reducing waste. For example, this invention may be used for preparing a compound of Formula 1

wherein

-   -   J is an optionally substituted carbon moiety; and     -   K is, together with the two contiguous linking carbon atoms, a         fused phenyl ring or a fused 5- or 6-membered heteroaromatic         ring, each ring optionally substituted.

More particularly, a compound of Formula 1 can be prepared by a method comprising: contacting a carboxylic acid of Formula 2 J-CO₂H  2 with a sulfonyl chloride of Formula 4 LS(O)₂Cl  4 wherein L is selected from alkyl, haloalkyl, and phenyl optionally substituted with from one to three substituents independently selected from alkyl or halogen; and with an isatoic anhydride of Formula 5

in the presence of a tertiary amine.

In the recitations herein, the term “tertiary amines” include trisubstituted amines, wherein the three substituents of the nitrogen are the same or different carbon moieties, and optionally substituted heteroaromatic amines. Examples of “trisubstituted amines” include triethylamine, N,N-diisopropylethylamine and N,N-dimethylaniline. The optionally substituted heteroaromatic amines include, but are not limited to, optionally substituted pyridines, quinoline and pyrimidines and 1,8-diazabicyclo[5.4.0]undec-7-ene. “Carbon moiety” refers to a radical in which a carbon atom is connected to the backbone of the fused oxazinone ring of Formula 1 and the carboxylic acid group of Formula 2. As the carbon moiety L is separated from the reaction center, it can encompass a great variety of carbon-based moieties that can be prepared by modern methods of synthetic organic chemistry. The method of this invention is generally applicable to prepare a wide range of compounds of Formula 1.

“Carbon moiety” thus includes alkyl, alkenyl and alkynyl moieties, which can be straight-chain or branched.

“Carbon moiety” also includes carbocyclic and heterocyclic rings, which can be saturated, partially saturated, or completely unsaturated. The carbocyclic and heterocyclic rings of a carbon moiety group can form polycyclic ring systems comprising multiple rings connected together. The term “carbocyclic ring” denotes a ring wherein the atoms forming the ring backbone are selected only from carbon. “Saturated carbocyclic” refers to a ring having a backbone consisting of carbon atoms linked to one another by single bonds; unless otherwise specified, the remaining carbon valences are occupied by hydrogen atoms. The term “hetero” in connection with rings or ring systems refers to a ring or ring system in which at least one ring atom is not carbon and which can contain from one to four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that each ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs. When the carbon moiety consists of a heterocyclic ring or ring system, it is connected to the backbone of the fused oxazinone ring of Formula 1 and the carboxylic acid group of Formula 2 through any available carbon ring atom by replacement of a hydrogen on said carbon atom. Heterocyclic rings or ring systems may also be connected to the carbon moiety through any available carbon or nitrogen atom by replacement of a hydrogen on said carbon or nitrogen atom.

Although there is no definite limit to the size of Formula 1 suitable for the process of the invention, typically Formula 1 comprises 9-100, more commonly 9-50, and most commonly 9-25 carbon atoms, and 3-25, more commonly 3-15, and most commonly 3-10 heteroatoms. Heteroatoms are atoms other than carbon or hydrogen and are commonly selected from halogen, oxygen, sulfur, nitrogen, phosphorus and silicon. Three heteroatoms in Formula 1 are the nitrogen atom and the two oxygen atoms in the oxazinone moiety. When K is a fused heteroaromatic ring or when the carbon moiety comprises a heterocyclic ring, additional heteroatoms are contained therein. Substituents attached to the K ring or the carbon moiety may also contain additional heteroatoms.

Unsaturated rings can be aromatic if Hückel's rule is satisfied. “Aromatic” indicates that each of the ring atoms is essentially in the same plane and has a p-orbital perpendicular to the ring plane, and in which (4n+2) π electrons, when n is 0 or a positive integer, are associated with the ring to comply with Hückel's rule. The term “aromatic ring system” denotes fully unsaturated carbocycles and heterocycles in which at least one ring of a polycyclic ring system is aromatic. The term “aromatic carbocyclic ring or ring system” includes fully aromatic carbocycles and carbocycles in which at least one ring of a polycyclic ring system is aromatic (e.g., phenyl, naphthyl and 1,2,3,4-tetrahydronaphthalenyl). The term “nonaromatic carbocyclic ring or ring system” denotes fully saturated carbocycles as well as partially or fully unsaturated carbocycles where the Hückel rule is not satisfied by any of the rings in the ring system. The terms “heteroaromatic ring or ring system” and “aromatic fused heterobicyclic ring system” includes fully aromatic heterocycles and heterocycles in which at least one ring of a polycyclic ring system is aromatic (where aromatic indicates that the Hückel rule is satisfied). The term “nonaromatic heterocyclic ring or ring system” denotes fully saturated heterocycles as well as partially or fully unsaturated heterocycles where the Hückel rule is not satisfied by any of the rings in the ring system. The term “aryl” denotes a carbocyclic or heterocyclic ring or ring system in which at least one ring is aromatic, and the aromatic ring provides the connection to the remainder of the molecule.

The carbon moiety specified for J is optionally substituted. Also, the K ring moieties of Formulae 1 and 5 are optionally substituted. Furthermore, the tertiary amines can be optionally substituted heteroaromatic amines. The term “optionally substituted” in connection with these groups refers to groups that are unsubstituted or have at least one non-hydrogen substituent. Illustrative optional substituents include alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, hydroxycarbonyl, formyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkoxycarbonyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, aryloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, arylthio, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, amino, alkylamino, alkenylamino, alkynylamino, arylamino, aminocarbonyl, alkylaminocarbonyl, alkenyl-aminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, alkylaminocarbonyl, alkenyl-aminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyloxy, alkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino and aryloxycarbonylamino, silyl moieties and siloxy moieties, each further optionally substituted; halogen; cyano; and nitro. The optional further substituents are independently selected from groups like those illustrated above for the substituents themselves to give additional substituent groups for J and K such as haloalkyl, haloalkenyl and haloalkoxy. As another example, alkylamino can be further substituted with alkyl, giving dialkylamino. The substituents can also be tied together by figuratively removing one or two hydrogen atoms from each of two substituents or a substituent and the supporting molecular structure and joining the radicals to produce cyclic and polycyclic structures fused or appended to the molecular structure supporting the substituents. For example, tying together adjacent hydroxy and methoxy groups attached to, for example, a phenyl ring gives a fused dioxolane structure containing the linking group —O—CH₂—O—. Tying together a hydroxy group and the molecular structure to which it is attached can give cyclic ethers, including epoxides. Illustrative substituents also include oxygen, which when attached to carbon forms a carbonyl function or when attached to nitrogen forms an N-oxide.

One skilled in the art will appreciate that not all nitrogen-containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen containing heterocycles which can form N-oxides. One skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist in Comprehensive Organic Synthesis, vol. 7, pp 748-750, S. V. Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol. 3, pp 18-20, A. J. Boulton and A. McKillop, Eds., Pergamon Press; M. R. Grimmett and B. R. T. Keene in Advances in Heterocyclic Chemistry, vol. 43, pp 149-161, A. R. Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advances in Heterocyclic Chemistry, vol. 9, pp 285-291, A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk in Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.

As referred to herein, “alkyl”, used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, and the different butyl, pentyl or hexyl isomers. “Alkenyl” includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. “Alkenyl” also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. “Alkynyl” includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. “Alkynyl” can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl. “Alkoxy” includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. “Alkenyloxy” includes straight-chain or branched alkenyloxy moieties. Examples of “alkenyloxy” include H₂C═CHCH₂O, (CH₃)₂C═CHCH₂O, (CH₃)CH═CHCH₂O, (CH₃)CH═C(CH₃)CH₂O and CH₂═CHCH₂CH₂O. “Alkynyloxy” includes straight-chain or branched alkynyloxy moieties. Examples of “alkynyloxy” include HC≡CCH₂O, CH₃C≡CCH₂O and CH₃C≡CCH₂CH₂O. “Alkylthio” includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. “Alkylsulfinyl” includes both enantiomers of an alkylsulfinyl group. Examples of “alkylsulfinyl” include CH₃S(O), CH₃CH₂S(O), CH₃CH₂CH₂S(O), (CH₃)₂CHS(O) and the different butylsulfinyl, pentylsulfinyl and hexylsulfinyl isomers. Examples of “alkylsulfonyl” include CH₃S(O)₂, CH₃CH₂S(O)₂, CH₃CH₂CH₂S(O)₂, (CH₃)₂CHS(O)₂ and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers. “Alkylamino”, “alkenylthio”, “alkenylsulfinyl”, “alkenylsulfonyl”, “alkynylthio”, “alkynylsulfinyl”, “alkynylsulfonyl”, and the like, are defined analogously to the above examples. Examples of “alkylcarbonyl” include C(O)CH₃, C(O)CH₂CH₂CH₃ and C(O)CH(CH₃)₂. Examples of “alkoxycarbonyl” include CH₃OC(═O), CH₃CH₂OC(═O), CH₃CH₂CH₂OC(═O), (CH₃)₂CHOC(═O) and the different butoxy- or pentoxycarbonyl isomers. “Cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term “cycloalkoxy” includes the same groups linked through an oxygen atom such as cyclopentyloxy and cyclohexyloxy. “Cycloalkylamino” means the amino nitrogen atom is attached to a cycloalkyl radical and a hydrogen atom and includes groups such as cyclopropylamino, cyclobutylamino, cyclopentylamino and cyclohexylamino. “(Alkyl)(cycloalkyl)amino” (or “(alkyl)cycloalkylamino”) means a cycloalkylamino group where the hydrogen atom is replaced by an alkyl radical; examples include groups such as (methyl)(cyclopropyl)amino, (butyl)(cyclobutyl)amino, (propyl)cyclopentylamino, (methyl)cyclohexylamino and the like. “Cycloalkenyl” includes groups such as cyclopentenyl and cyclohexenyl as well as groups with more than one double bond such as 1,3- and 1,4-cyclohexadienyl.

The term “halogen”, either alone or in compound words such as “haloalkyl”, includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” include F₃C, ClCH₂, CF₃CH₂ and CF₃CCl₂.

The term “silyl moieties” refers to moieties containing at least one silicon atom bonded to the remainder of Formula 1 through said silicon atom and includes groups such as trialkylsilyl (examples include trimethylsilyl, triisopropylsilyl and dimethyl-t-butylsilyl) and dialkylarylsilyl groups (e.g. dimethylphenylsilyl). The term “siloxy moieties” refers to moieties containing at least one silicon atom bonded to an oxygen atom and connected to the remainder of Formula 1 through said oxygen atom and includes groups such as trialkylsiloxy (examples include trimethylsiloxy, triisopropylsiloxy and dimethyl-t-butylsiloxy) and dialkylarylsilyl groups (e.g. dimethylphenylsiloxy).

The total number of carbon atoms in a substituent group is indicated by the “C_(i)-C_(j)” prefix where i and j are, for example, numbers from 1 to 3; e.g., C₁-C₃ alkyl designates methyl through propyl.

Of note as tertiary amines are optionally substituted pyridines. There is no definite limit to the nature and size of the substituents on the pyridine, but the substituents are commonly alkyl, more particularly C₁-C₆, more commonly C₁-C₄, and most commonly C₁ (i.e. methyl). Typical examples of optionally substituted pyridines are pyridine, the picolines (i.e. 2-methylpyridine, 3-methylpyridine, 4-methylpyridine), the lutidines (e.g., 2,3-dimethylpyridine, 2,4-dimethylpyridine, 2,5-dimethylpyridine, 2,5-dimethylpyridine, 3,4-dimethylpyridine, 3,5-dimethylpyridine) and collidine. Other common substituents are dimethylamino (e.g., 4-(dimethylamino)pyridine) and pyrrolidino (e.g., 4-(pyrrolidino)pyridine). Furthermore, two substituents on pyridine can be tied together as already described to form other common pyridine derivatives, such as quinoline and isoquinoline. These quinoline and isoquinoline pyridine derivatives can also be further substituted.

Although there is no definite limit to the size of J, optionally substituted alkyl moieties in J commonly include 1 to 6 carbon atoms, more commonly 1 to 4 carbon atoms, and most commonly 1 or 2 carbon atoms in the alkyl chain. Similarly, optionally substituted alkenyl and alkynyl moieties in J commonly include 2 to 6 carbon atoms, more commonly 2 to 4 carbon atoms, and most commonly 2 or 3 carbon atoms in the alkenyl or alkynyl chain.

As indicated above, the carbon moiety J may be (among others) an aromatic ring or ring system. Examples of aromatic rings or ring systems include a phenyl ring, 5- or 6-membered heteroaromatic rings, aromatic 8-, 9- or 10-membered fused carbobicyclic ring systems and aromatic 8-, 9- or 10-membered fused heterobicyclic ring systems, wherein each ring or ring system is optionally substituted. The term “optionally substituted” in connection with these J groups refers to groups that are unsubstituted or have at least one non-hydrogen substituent. These carbon moieties may be substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, the number of optional substituents (when present) ranges from one to four. An example of phenyl optionally substituted with from one to four substituents is the ring illustrated as U-1 in Exhibit 1, wherein R^(v) is any substituent and r is an integer from 0 to 4. Examples of aromatic 8-, 9- or 10-membered fused carbobicyclic ring systems optionally substituted with from one to four substituents include a naphthyl group optionally substituted with from one to four substituents illustrated as U-85 and a 1,2,3,4-tetrahydronaphthyl group optionally substituted with from one to four substituents illustrated as U-86 in Exhibit 1, wherein R^(v) is any substituent r is an integer from 0 to 4. Examples of 5- or 6-membered heteroaromatic rings optionally substituted with from one to four substituents include the rings U-2 through U-53 illustrated in Exhibit 1 wherein R^(v) is any substituent and r is an integer from 0 to 4. Examples of aromatic 8-, 9- or 10-membered fused heterobicyclic ring systems optionally substituted with from one to four substituents include U-54 through U-84 illustrated in Exhibit 1 wherein R^(v) is any substituent and r is an integer from 0 to 4. Other examples of J include a benzyl group optionally substituted with from one to four substituents illustrated as U-87 and a benzoyl group optionally substituted with from one to four substituents illustrated as U-88 in Exhibit 1, wherein R^(v) is any substituent and r is an integer from 0 to 4.

Although R^(v) groups are shown in the structures U-1 through U-88, it is noted that they do not need to be present since they are optional substituents. The nitrogen atoms that require substitution to fill their valence are substituted with H or R^(v). Note that some U groups can only be substituted with less than 4 R^(v) groups (e.g. U-14, U-15, U-18 through U-21 and U-32 through U-34 can only be substituted with one R^(v)). Note that when the attachment point between (R^(v))_(r) and the U group is illustrated as floating, (R^(v))_(r) can be attached to any available carbon atom or nitrogen atom of the U group. Note that when the attachment point on the U group is illustrated as floating, the U group can be attached to the remainder of Formula I through any available carbon of the U group by replacement of a hydrogen atom.

As indicated above, the carbon moiety J may be (among others) saturated or partially saturated carbocyclic and heterocyclic rings, which can be further optionally substituted. The term “optionally substituted” in connection with these J groups refers to groups that are unsubstituted or have at least one non-hydrogen substituent. These carbon moieties may be substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, the number of optional substituents (when present) ranges from one to four. Examples of saturated or partially saturated carbocyclic rings include optionally substituted C₃-C₈ cycloalkyl and optionally substituted C₃-C₈ cycloalkenyl. Examples of saturated or partially saturated heterocyclic rings include optionally substituted 5- or 6-membered nonaromatic heterocyclic rings optionally including one or two ring members selected from the group consisting of C(═O), SO or S(O)₂. Examples of such J groups include those illustrated as G-1 through G-35 in Exhibit 2. Note that when the attachment point on these G groups is illustrated as floating, the G group can be attached to the remainder of Formula 1 through any available carbon or nitrogen of the G group by replacement of a hydrogen atom. The optional substituents can be attached to any available carbon or nitrogen by replacing a hydrogen atom (said substituents are not illustrated in Exhibit 2 since they are optional substituents). Note that when G comprises a ring selected from G-24 through G-31, G-34 and G-35, Q² may be selected from O, S, NH or substituted N.

It is noted that the J group may be optionally substituted. As noted above, a J group may commonly comprise a U group or a G group further substituted with from one to four substituents. Thus J groups may comprise a U group or a G group selected from U-1 through U-88 or G-1 through G-35, and further substituted with additional substituents including from one to four U or G groups (which may be the same or different) and both the core U or G group and substituent U or G groups optionally further substituted. Of note are J groups comprising a U or G group substituted with one U or G group and optionally substituted with from one to three additional substituents. For example, J can be U-11, in which an R^(v) attached to the 1-nitrogen is the group U-41.

As noted above, K is, together with the two contiguous linking carbon atoms, a fused phenyl ring or a fused, 5- or 6-membered heteroaromatic ring, each ring optionally substituted. The term “optionally substituted” in connection with these K rings refers to K rings that are unsubstituted or have at least one non-hydrogen substituent. An example of a K ring wherein the K ring is optionally substituted with from one to four R^(t) includes the ring system illustrated as K-38 (fused phenyl ring) in Exhibit 3 wherein n is an integer from 0 to 4 and R^(t) is any substituent. Examples of said K rings wherein the K ring is optionally substituted with from one to three R^(t) include the ring systems K-1 to K-37 (5- or 6-membered heteroaromatic rings) in Exhibit 3, wherein n is an integer from 0 to 3 and R^(t) is any substituent. As with the carbon atoms in the ring, the nitrogen atoms that require substitution to fill their valence are substituted with hydrogen or with R^(t). Although (R^(t))_(n) groups are shown in the structures K-1 to K-38, it is noted that R^(t) does not need to be present since it is an optional substituent. Note that some K rings can only be substituted with less than 3 R^(t) groups (e.g. K-7 through K-10, K-15, K-16, K-20, K-21, K-23, K-24, K-26 and K-27 can only be substituted with one R^(t)). In the exemplified K groups, the upper right bond is attached through the available linking carbon atom to the nitrogen atom of the oxazinone portion of Formula 1 and the lower right bond is attached through the available linking carbon atom to the carbonyl atom of the oxazinone portion of Formula 1. The wavy line indicates that the K ring is attached to the remainder of Formula 1 as illustrated below.

Of note are K rings including optionally substituted thiophene, isoxazole, isothiazole, pyrazole, pyridine and pyrimidine rings. Of particular note are K rings K-1, K-14, K-15, K-18, K-23, K-28, K-29, K-30, K-31 and K-33, especially K-28, K-31 and K-33. Also of particular note is K-38 (optionally substituted phenyl).

Examples of optional substituents that can be attached to the U, G or K groups illustrated above include substituents selected from W. The K rings may also be substituted with the previously described optionally substituted U or optionally substituted G groups.

-   -   Each W is independently C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄         alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl,         C₂-C₄ haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂, C₁-C₄         alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,         C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆         cycloalkylamino, (C₁-C₄ alkyl)(C₃-C₆ cycloalkyl)amino or C₃-C₆         trialkylsilyl.

Other suitable substituents include

-   -   B(OR¹⁷)₂; NH₂; SH; thiocyanato; C₃-C₈ trialkylsilyloxy; C₁-C₄         alkyldisulfide; SF₅; R¹⁹C(=E)-; R¹⁹C(=E)M-; R¹⁹MC(=E)-;         (R¹⁹)MC(=E)M-; —OP(=Q)(OR¹⁹)₂; —S(O)₂MR¹⁹; R¹⁹S(O)₂M-;         wherein     -   each E is independently O, S, NR¹⁵, NOR¹⁵, NN(R¹⁵)₂, N—S═O, N—CN         or N—NO₂;     -   each M is independently O, NR¹⁸ or S;     -   Q is O or S;     -   each R¹⁵ and each R¹⁹ is independently H; C₁-C₆ alkyl optionally         substituted with one or more substituents selected from the         group consisting of CN, NO₂, hydroxy, C₁-C₄ alkoxy, C₁-C₄         haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄         alkylsulfonyl, C₁-C₄ haloalkylthio, C₁-C₄ haloalkylsulfinyl,         C₁-C₄ haloalkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino,         CO₂H, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylcarbonyl, C₃-C₆         trialkylsilyl, and a phenyl ring optionally substituted with one         to three substituents independently selected from W; C₁-C₆         haloalkyl; C₃-C₆ cycloalkyl; or a phenyl ring optionally         substituted with from one to three substituents independently         selected from W;     -   each R¹⁷ is independently H or C₁-C₄ alkyl; or     -   B(OR¹⁷)₂ can form a ring wherein the two oxygen atoms are linked         by a chain of two to three carbons optionally substituted with         one or two substituents independently selected from methyl or         C₂-C₆ alkoxycarbonyl; and     -   each R¹⁸ is independently H, C₁-C₆ alkyl or C₁-C₆ haloalkyl.

Of note are methods for preparing compounds of Formula 1 wherein J is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl, each optionally substituted; or J is a phenyl ring, a benzyl group, a benzoyl group, a 5- or 6-membered heteroaromatic ring, an aromatic 8-, 9- or 10-membered fused carbobicyclic ring system, an aromatic 8-, 9- or 10-membered fused heterobicyclic ring system or a 5- or 6-membered nonaromatic heterocyclic ring optionally including one or two ring members selected from the group consisting of C(═O), SO or S(O)₂, each optionally substituted. Of particular note are such methods wherein

-   -   K is, together with the two contiguous linking carbon atoms, a         fused phenyl ring optionally substituted with from one to four         substituents independently selected from G, U, W or R¹³; or a         fused 5- or 6-membered heteroaromatic ring optionally         substituted with from one to three substituents independently         selected from G, U, W or R¹³;     -   J is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl         or C₃-C₈ cycloalkenyl, each optionally substituted with one or         more substituents selected from the group consisting of R¹²,         halogen, CN, NO₂, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylsulfinyl,         C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆         cycloalkylamino and (C₁-C₄ alkyl)(C₃-C₆ cycloalkyl)amino; or     -   J is a phenyl ring, a benzyl group, a benzoyl group, a 5- or         6-membered heteroaromatic ring, an aromatic 8-, 9- or         10-membered fused carbobicyclic ring system, an aromatic 8-, 9-         or 10-membered fused heterobicyclic ring system or a 5- or         6-membered nonaromatic heterocyclic ring optionally including         one or two ring members selected from the group consisting of         C(═O), SO or S(O)₂, each optionally substituted with from one to         four substituents independently selected from G, U, W or R¹³;     -   each G is a 5- or 6-membered nonaromatic heterocyclic ring         optionally including one or two ring members selected from the         group consisting of C(═O), SO or S(O)₂, each optionally         substituted with from one to four substituents independently         selected from W;     -   each U is a phenyl ring, a benzyl group, a benzoyl group, a 5-         or 6-membered heteroaromatic ring, an aromatic 8-, 9- or         10-membered fused carbobicyclic ring system, an aromatic 8-, 9-         or 10-membered fused heterobicyclic ring system, each optionally         substituted with from one to four substituents independently         selected from W;     -   each W is independently C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄         alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl,         C₂-C₄ haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂, C₁-C₄         alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,         C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆         cycloalkylamino, (C₁-C₄ alkyl)(C₃-₆ cycloalkyl)amino or C₃-C₆         trialkylsilyl;     -   each R¹² is independently R¹⁹C(=E)-; R¹⁹C(=E)L-; R¹⁹LC(=E);         (R¹⁹)LC(=E)L-; —O(Q=)P(OR¹⁹)₂; —SO₂LR¹⁸; or R¹⁹SO₂L-;     -   each R¹³ is B(OR¹⁷)₂; NH₂; SH; thiocyanato; C₃-C₈         trialkylsilyloxy; C₁-C₄ alkyldisulfide; SF₅; R¹⁹C(=E)-;         R¹⁹C(=E)M-; R¹⁹MC(=E)-; (R¹⁹)MC(=E)M-; —OP(=Q)(OR¹⁹)₂;         —S(O)₂MR¹⁹; R¹⁹S(O)₂M-;     -   each E is independently O, S, NR¹⁵, NOR¹⁵, NN(R¹⁵)₂, N—S═O, N—CN         or N—NO₂;     -   each M is independently O, NR¹⁸ or S;     -   Q is O or S;     -   each R¹⁵ and each R¹⁹ is independently H; C₁-C₆ alkyl optionally         substituted with one or more substituents selected from the         group consisting of CN, NO₂, hydroxy, C₁-C₄ alkoxy, C₁-C₄         haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄         alkylsulfonyl, C₁-C₄ haloalkylthio, C₁-C₄ haloalkylsulfinyl,         C₁-C₄ haloalllylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino,         CO₂H, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylcarbonyl, C₃-C₆         trialkylsilyl, and a phenyl ring optionally substituted with one         to three substituents independently selected from W; C₁-C₆         haloalkyl; C₃-C₆ cycloalkyl; or a phenyl ring optionally         substituted with from one to three substituents independently         selected from W;     -   each R¹⁷ is independently H or C₁-C₄ alkyl; or     -   B(OR¹⁷)₂ can form a ring wherein the two oxygen atoms are linked         by a chain of two to three carbons optionally substituted with         one or two substituents independently selected from methyl or         C₂-C₆ alkoxycarbonyl; and     -   each R¹⁸ is independently H, C₁-C₆ alkyl or C₁-C₆ haloalkyl.

Preferably, K is, together with the two contiguous linking carbon atoms, a fused phenyl ring optionally substituted with from one to four substituents independently selected from W or R¹³.

The compounds of Formula 1 can be prepared by one or more of the following methods and variations as described in Schemes 1-27. The definitions of J, K, L, M, R⁴, through R⁹, R^(v) X, Y and n in the compounds of Formulae 2-76 below are as defined above. Compounds of Formulae 1a, 2′, and 2a-p, 5′, 9a-b and 25a-c are various subsets of the compounds of Formula 1, 2, 5, 9 and 25, respectively. Of note are compounds wherein K is selected from the group consisting of optionally substituted thiophene, isoxazole, isothiazole, pyrazole, pyridine and pyrimidine rings. Also of note are compounds wherein K is K-1, K-14, K-15, K-18, K-23, K-28, K-29, K-30, K-31 and K-33. Of particular note are compounds wherein K is K-28, K-31 and K-33. Also of particular note are. compounds wherein K is an optionally substituted fused phenyl ring (K-38).

As shown in Scheme 1, according to the method of this invention a fused oxazinone of Formula 1 is prepared via coupling of a carboxylic acid of Formula 2 with an isatoic anhydride of Formula 5 in the presence of a sulfonyl chloride 4 and a tertiary amine 3 in a suitable solvent.

The reaction components can be added to the reaction vessel in various sequences or added as mixtures. Suitable solvents include aromatic hydrocarbons such as chlorobenzene or toluene, and preferred solvents include esters such as ethyl acetate or butyl acetate; ketones such as acetone, 2-butanone, or 4methyl-2-pentanone; ethers such as tetrahydrofuran (THF) or dioxane; nitriles such as acetonitrile; and halocarbons such as dichloromethane or chloroform. More preferred solvents include acetonitrile, ethyl acetate, acetone, THF and dichioromethane. Most preferred solvents are acetonitrile and acetone. The reaction is typically conducted at temperatures ranging from −30° C. to +100° C. Preferred is the addition to the reaction vessel (charging) of all components at temperatures from −10° C. to +5° C., with intervening periods of from 1 to 30 minutes (preferred are intervening periods of from 5 to 15 minutes) between additions followed by warming the reaction mixture to from +20° C. to +50° C. for 0.5 to 24 hours (preferably 2 to 4 hours). Charging of a component (for example, a reactant, a solvent, etc.) means adding the component during the step. One of ordinary skill in the art will recognize that a component may be added (i.e. charged) in various ways, for example as a batch, intermittent or continuous feed depending on process design. The nominal mole ratio of the Formula 4 compound to the Formula 2 compound is typically from about 1.0 to 1.5, and preferably is from about 1.1 to 1.3. Preferred Formula 4 compounds include methanesulfonyl chloride, propanesulfonyl chloride and benzenesulfonyl chloride. Methanesulfonyl chloride is more preferred for reasons of lower cost and/or less waste. The nominal mole ratio of the Formula 3 compound charged to the Formula 2 compound charged is typically from about 2.0 to 4.0, and is preferably from about 2.8 to 3.4. The nominal mole ratio of the Formula 5 compound to the Formula 2 compound is typically from about 0.9 to 1.1, and is preferably about 1.0. Preferred Formula 3 compounds include 2-picoline, 3-picoline, 2,6-lutidine, and pyridine. The compounds of Formulae 2, 3, 4 and 5 can be combined in any order or as a mixture in solvent.

Preferred methods of this invention include the method wherein the carboxylic acid of Formula 2 is Formula 2′, the isatoic anhydride of Formula 5 is Formula 5′ and the product compound of Formula 1 is Formula 1a as shown in Scheme 2.

wherein

-   -   X is N or CR⁶;     -   Y is N or CH;     -   R⁴ is C₁-C₄ alkyl or halogen;     -   R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, CN or halogen;     -   R⁶ and R⁷ are independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl,         halogen, CN or C₁-C₄ haloalkoxy;     -   R⁸ is H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆         cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl, C₂-C₄         haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂, C₁-C₄         alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,         C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆         cycloalkylamino, (C₁-C₄ alkyl)(C₃-C₆ cycloalkyl)amino, C₂-C₄         alkylcarbonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl,         C₃-C₈ dialkylaminocarbonyl or C₃-C₆ trialkylsilyl;     -   R⁹ is CF₃, OCF₃, OCHF₂, OCH₂CF₃, S(O)_(p)CF₃, S(O)_(p)CHF₂ or         halogen; and     -   p is 0, 1 or 2.

Compounds of Formula 1a may be prepared in this way and used for preparing compounds of Formula III.

Isatoic anhydrides of Formula 5 can be made by a variety of known methods which are well documented in the chemical literature. For example, isatoic anhydrides are available from the corresponding anthranilic acids via cyclization involving reaction of the anthranilic acid with phosgene or a phosgene equivalent. For leading references to the methods see, Coppola, Synthesis 1980, 505 and Fabis et al., Tetrahedron, 1998, 10789.

The synthesis of the isatoic anhydrides of Formula 5′ can be achieved from isatins of Formula 7 as outlined in Scheme 3.

Isatins of Formula 7 are available from aniline derivatives of Formula 6 following literature procedures such as F. D. Popp, Adv. Heterocycl. Chem. 1975, 18, 1-58 and J. F. M. Da Silva et al., Journal of the Brazilian Chemical Society 2001, 12(3), 273-324. Oxidation of isatin 7 with hydrogen peroxide generally affords good yields of the corresponding isatoic anhydride 5′ (G. Reissenweber and D. Mangold, Angew. Chem. Int. Ed. Engl. 1980, 19,222-223).

As shown in Scheme 4, isatoic anhydrides of Formula 5′ (compounds of Formula 5 wherein K is a fused phenyl ring with substituents R⁴ and R⁵) are typically available from the corresponding 2-nitrobenzoic acids (or esters) of Formula 9 via catalytic hydrogenation of the nitro group followed by reaction with phosgene or a phosgene equivalent. Typical reduction procedures involve reduction with hydrogen in the presence of a metal catalyst such as palladium on carbon or platinum oxide in hydroxylic solvents such as ethanol and isopropanol. The reduction can also be conducted in the presence of zinc in acetic acid. These methods for reducing nitro groups are well documented in the chemical literature.

As shown in Scheme 5, anthranilic acids containing an R⁵ substituent of chloro, bromo or iodo can be prepared by direct halogenation of an anthranilic acid of Formula 9a with N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS) respectively in solvents such as N,N-dimethylformamide (DMF) to produce the corresponding substituted acid of Formula 9b.

Benzoic acids of Formula 2 (wherein J is optionally substituted phenyl) are generally well known in the art as are procedures for their preparation.

Benzoic acids of Formula 2a may be prepared from the benzonitriles of Formula 10 by hydrolysis (Scheme 6). The conditions used may involve the use of a base such as an alkline metal hydroxide or alkoxide (e.g., potassium or sodium hydroxide) in a solvent such as water, ethanol or ethylene glycol (see e.g., J. Chem. Soc. 1948, 1025). Alternatively, the hydrolysis may be carried out using an acid such as sulfuric acid or phosphoric acid in a suitable solvent such as water (see e.g., Org. Synth. 1955, Coll vol. 3, 557). The choice of the conditions is contingent on the stability of any optional substituents present on the aromatic ring to the reaction conditions, and elevated temperatures are usually employed to achieve this transformation.

Nitriles of Formula 10 may be prepared from anilines of Formula 11 by the classical sequence involving diazotization and treatment of the intermediate diazonium salt with a copper cyanide salt (see e.g., J. Amer. Chem Soc. 1902, 24, 1035).

Certain heterocyclic acids of Formula 2, wherein J is an optionally substituted heterocycle, can be prepared by procedures outlined in Schemes 8 through 27. Both general and specific references to a wide variety of heterocyclic acids including thiophenes, furans, pyridines, pyriridines, triazoles, imidazoles, pyrazoles, thiazoles, oxazoles, isothiazoles, thiadiazoles, oxadiazoles, triazines, pyrazines, pyridazines, and isoxazoles can be found in the following compendia: Rodd's Chemistry of Chemistry of Carbon Compounds, Vol. IVa to IV1., S. Coffey editor, Elsevier Scientific Publishing, New York, 1973; Comprehensive Heterocyclic Chemistry, Vol. 1-7, A. R. Katritzky and C. W. Rees editors, Pergamon Press, New York, 1984; Comprehensive Heterocyclic Chemistry II, Vol. 1-9, A. R. Katritzky, C. W. Rees, and E. F. Scriven editors, Pergamon Press, New York, 1996; and the series, The Chemistry of Heterocyclic Compounds, E. C. Taylor, editor, Wiley, New York. Noteworthy heterocyclic acids suitable for use in this invention include pyridine acids, pyrimidine acids, pyrazole acids and pyrrole acids. Procedures for the synthesis of representative examples of each are detailed in Schemes 8 through 27. A variety of heterocyclic acids and general methods for their synthesis may be found in PCT Patent Publication WO 98/57397.

The synthesis of representative pyridine acids of Formula 2b is depicted in Scheme 8. This procedure involves the known synthesis of pyridines from β-ketoesters (Formula 16) and 4-aminobutenones (Formula 15). Substituent groups R^(a) and R^(b) include, for example, alkyl, haloalkyl, and optionally substituted aromatic and heteroaromatic rings.

The synthesis of representative pyrimidine acids (Formula 2c) is depicted in Scheme 9. This procedure involves the known synthesis of pyrimidines from vinylidene-β-ketoesters (Formula 16) and amidines (Formula 20). Substituent groups R^(a) and R^(b) include, for example, alkyl, haloalkyl, and optionally substituted aromatic and heteroaromatic rings.

Syntheses of representative pyrazole acids (Formula 2d-2g) are depicted in Schemes 10 through 13. The synthesis of 2d in Scheme 10 involves as the key step introduction of the R^(a) substituent via alkylation of the pyrazole. The alkylating agent R^(a)-Lg (wherein Lg is a leaving group such as Cl, Br, I, sulfonates such as p-toluenesulfonate, methanesulfonate or trifluoromethanesulfonate, or sulfates such as —SO₂OR^(a)) includes R^(a) groups such as C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₂-C₆ haloalkynyl, C₃-C₆ halocycloalkyl, C₂-C₆ alkylcarbonyl, C₂-C₆ alkoxycarbonyl, C₃-C₈ dialkylamino-carbonyl, C₃-C₆ trialkylsilyl; or phenyl, benzyl, benzoyl, 5- or 6-membered heteroaromatic rings or aromatic 8-, 9- or 10-membered fused heterobicyclic ring systems, each ring or ring system optionally substituted. (As referred to herein, the terms “alkylation” and “alkylating agent” are not limited to R^(a) being an alkyl group.) Oxidation of the methyl group affords the pyrazole carboxylic acid. Some notable R^(b) groups include haloalkyl.

Alkylation of pyrazoles using potassium carbonate and N,N-dimethylformamide (DM) are described by T. Kitazaki et al., Chem. Pharm. Bull. 2000, 48(12), 1935-1946. One skilled in the art recognizes that a variety of bases and solvents can be used for alkylation of pyrazoles. For example, C. T. Alabaster et al., J. Med. Chem. 1989, 32, 575-583 discloses use of sodium carbonate in DMP, X. Wang et al., Org. Lett. 2000, 2(20), 3107-3109 discloses use of potassium tert-butoxide in methyl sulfoxide, and European Patent Application Publication EP-1081146-A1 describes the use of methyl sulfoxide and sodium or potassium hydroxide in the presence of a phase transfer catalyst or cesium carbonate. One skilled in the art also recognizes that a variety of alternative synthetic methods are applicable to the coupling of a pyrazole of Formula 22 to form a pyrazole of Formula 24 (or coupling of a pyrazole of Formula 25 below to form a pyrazole of Formula 26 below). These methods include, for example, condensation with aryl iodides in the presence of copper(I) iodide and trans-cyclohexanediamine as reported by A. Klapars, J. C. Antilla, X. Huang and S. L. Buchwald, J. Am. Chem. Soc. 2001, 123, 7727-7729, and condensation with aryl boronic acids in the presence of copper(II) acetate and pyridine as reported by P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters, D. M. T. Chan and A. Combs, Tetrahedron Lett. 1998, 39, 2941-2944.

Some pyrazole acids of Formula 2d may be prepared via metallation and carboxylation of pyrazoles of Formula 26 as the key step (Scheme 11). This reaction is typically conducted by treating compounds of Formula 25 with lithium diisopropylamide (LDA) to form an anion and then contacting the anion with carbon dioxide. The R^(a) group is introduced in a manner similar to that of Scheme 10, i.e. via alkylation with an R^(a) alkylating agent. Representative R^(b) groups include, for example, cyano and haloalkyl.

This procedure is particularly useful for preparing 1-(2-pyridinyl)pyrazolecarboxylic acids of Formula 2e, wherein R^(a) is a substituted 2-pyridinyl ring, as shown in Scheme 12. Reaction of a pyrazole of Formula 27 with a 2-halopyridine of Formula 28 affords good yields of the 1-pyridinylpyrazole of Formula 29 with good specificity for the desired regiochemistry. Metallation of 29 with LDA followed by quenching of the lithium salt with carbon dioxide affords the 1-(2-pyridinyl)pyrazolecarboxylic acid of Formula 2e. For a leading reference to this method see, WO 03/015519.

-   -   wherein R⁷ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, halogen, CN or         C₁-C₄ haloalkoxy; and     -   R⁹ is CF₃, OCF₃, OCHF₂, OCH₂CF₃, S(O)_(p)CF₃, S(O)_(p)CHF₂ or         halogen.

Other pyrazoles of Formula 2d can be prepared via reaction of hydrazine of Formula 31 with a pyruvate of Formula 30 to yield pyrazole esters of Formula 32 (Scheme 13). Hydrolysis of the ester affords the pyrazole acids 2d. This procedure is particularly useful for the preparation of compounds wherein R^(a) is optionally substituted phenyl and R^(b) is haloalkyl.

Pyrazole acids of Formula 2d can also be prepared via 3+2 cycloaddition of an appropriately substituted iminohalide of Formula 33 with either substituted propiolates of Formula 34 or acrylates of Formula 35 (Scheme 14). Cycloaddition with acrylates requires additional oxidation of the intermediate pyrazoline to the pyrazole. Hydrolysis of the ester of Formula 36 affords the pyrazole acids 2d. Preferred iminohalides for this reaction include the trifluoromethyl iminochloride (37) and the iminodibromide (38). Compounds such as 37 are known (J. Heterocycl. Chem. 1985, 22(2), 565-8). Compounds such as 38 are available by known methods (Tetrahedron Letters 1999, 40, 2605). These procedures are particularly useful for the preparation of compounds where R^(a) is optionally substituted phenyl and R^(b) is haloalkyl or bromo.

The starting pyrazoles of Formula 25 are known compounds or can be prepared according to known methods. The pyrazole of Formula 25a (the compound of Formula 25 wherein R^(b) is CF₃) can be prepared by literature procedures (J. Fluorine Chem. 1991, 53(1), 61-70). The pyrazoles of Formula 25b (compounds of Formula 25 wherein R^(b) is Cl or Br) can be prepared by literature procedures (Chem. Ber. 1966, 99(10), 3350-7). A useful alternative method for the preparation of a compound of Formula 25b is depicted in Scheme 15. Metallation of the sulfamoyl pyrazole of Formula 39 with n-butyllithium followed by direct halogenation of the anion with either hexachloroethane (for R^(b) being Cl) or 1,2-dibromotetrachloroethane (for R^(b) being Br) affords the halogenated derivatives of Formula 40. Removal of the sulfamoyl group with trifluoroacetic acid (TFA) at room temperature proceeds cleanly and in good yield to afford the pyrazoles of Formula 25c. One skilled in the art will recognize that Formula 25c is a tautomer of Formula 25b.

Pyrazolecarboxylic acids of Formula 2f wherein R¹⁰ is CF₃ can be prepared by the method outlined in Scheme 16.

Reaction of a compound of Formula 41 wherein R¹⁰ is C₁-C₄ alkyl with a suitable base in a suitable organic solvent affords the cyclized product of Formula 42 after neutralization with an acid such as acetic acid. The suitable base can be, for example but not limitation, sodium hydride, potassium t-butoxide, dimsyl sodium (CH₃S(O)CH₂ ⁻Na⁺), alkali metal (such as lithium, sodium or potassium) carbonates or hydroxides, tetraalkyl (such as methyl, ethyl or butyl)ammonium fluorides or hydroxides, or 2-tert-butylimino-2-diethyl-amino-1,3-dimethyl-perhydro-1,3,2-diazaphosphonine. The suitable organic solvent can be, for example but not limitation, acetone, acetonitrile, tetrahydrofuran, dichloromethane, dimethylsulfoxide, or N,N-dimethylformamide. The cyclization reaction is usually conducted in a temperature range from about 0 to 120° C. The effects of solvent, base, temperature and addition time are all interdependent, and choice of reaction conditions is important to minimize the formation of byproducts. A preferred base is tetrabutyl-ammonium fluoride.

Dehydration of the compound of Formula 42 to give the compound of Formula 43, followed by converting the carboxylic ester function to carboxylic acid, affords the compound of Formula 2f. The dehydration is effected by treatment with a catalytic amount of a suitable acid. This catalytic acid can be, for example but not limitation, sulfuric acid. The reaction is generally conducted using an organic solvent. As one skilled in the art will realize, dehydration reactions may be conducted in a wide variety of solvents in a temperature range generally between about 0 and 200° C., more preferably between about 0 and 100° C. For the dehydration in the method of Scheme 16, a solvent comprising acetic acid and temperatures of about 65° C. are preferred. Carboxylic ester compounds can be converted to carboxylic acid compounds by numerous methods including nucleophilic cleavage under anhydrous conditions or hydrolytic methods involving the use of either acids or bases (see T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York, 1991, pp. 224-269 for a review of methods). For the method of Scheme 16, base-catalyzed hydrolytic methods are preferred. Suitable bases include alkali metal (such as lithium, sodium or potassium) hydroxides. For example, the ester can be dissolved in a mixture of water and an alcohol such as ethanol. Upon treatment with sodium hydroxide or potassium hydroxide, the ester is saponified to provide the sodium or potassium salt of the carboxylic acid. Acidification with a strong acid, such as hydrochloric acid or sulfuric acid, yields the carboxylic acid of Formula 2f. The carboxylic acid can be isolated by methods known to those skilled in the art, including crystallization, extraction and distillation.

Compounds of Formula 41 can be prepared by the method outlined in Scheme 17.

-   -   wherein R⁹ is CF₃ and R¹⁰ is C₁-C₄ alkyl.         Treatment of a hydrazine compound of Formula 44 with a ketone of         Formula 45 in a solvent such as water, methanol or acetic acid         gives the hydrazone of Formula 46. One skilled in the art will         recognize that this reaction may require catalysis by an         optional acid and may also require elevated temperatures         depending on the molecular substitution pattern of the hydrazone         of Formula 46. Reaction of the hydrazone of Formula 46 with the         compound of Formula 47 in a suitable organic solvent such as,         for example but not limitation, dichloromethane or         tetrahydrofuran in the presence of an acid scavenger such as         triethylamine provides the compound of Formula 41. The reaction         is usually conducted at a temperature between about 0 and         100° C. Hydrazine compounds of Formula 44 can be prepared by         standard methods, such as by contacting the corresponding halo         compound of Formula 28 (Scheme 12) with hydrazine.

Pyrazolecarboxylic acids of Formula 2g wherein R⁹ is halogen such as Cl or Br can be prepared by the method outlined in Scheme 18.

wherein R¹⁰ is C₁-C₄ alkyl.

Oxidation of the compound of Formula 48 optionally in the presence of acid to give the compound of Formula 49 followed by conversion of the carboxylic ester function to the carboxylic acid provides the compound of Formula 2g. The oxidizing agent can be hydrogen peroxide, organic peroxides, potassium persulfate, sodium persulfate, ammonium persulfate, potassium monopersulfate (e.g., Oxone®) or potassium permanganate. To obtain complete conversion, at least one equivalent of oxidizing agent versus the compound of Formula 48 should be used, preferably between about one to two equivalents. This oxidation is typically carried out in the presence of a solvent. The solvent can be an ether, such as tetrahydrofuran, p-dioxane and the like, an organic ester, such as ethyl acetate, dimethyl carbonate and the like, or a polar aprotic organic such as N,N-dimethylformamide, acetonitrile and the like. Acids suitable for use in the oxidation step include inorganic acids, such as sulfuric acid, phosphoric acid and the like, and organic acids, such as acetic acid, benzoic acid and the like. The acid, when used, should be used in greater than 0.1 equivalents versus the compound of Formula 48. To obtain complete conversion, one to five equivalents of acid can be used. The preferred oxidant is potassium persulfate, and the oxidation is preferably carried out in the presence of sulfuric acid. The reaction can be carried out by mixing the compound of Formula 48 in the desired solvent and, if used, the acid. The oxidant can then be added at a convenient rate. The reaction temperature is typically varied from as low as about 0° C. up to the boiling point of the solvent in order to obtain a reasonable reaction time to complete the reaction, preferably less than 8 hours. The desired product, a compound of Formula 49, can be isolated by methods known to those skilled in the art, including crystallization, extraction and distillation. Methods suitable for converting the ester of Formula 49 to the carboxylic acid of Formula 2g are already described for Scheme 16.

Compounds of Formula 48 wherein R⁹ is halogen such as Cl or Br can be prepared from corresponding compounds of Formula 50 as shown in Scheme 19.

wherein R¹⁰ is C₁-C₄ alkyl.

Treatment of a compound of Formula 50 with a halogenating reagent, usually in the presence of a solvent, affords the corresponding halo compound of Formula 48 (R⁹ is halogen). Halogenating reagents that can be used include phosphorus oxyhalides, phosphorus trihalides, phosphorus pentahalides, thionyl chloride, dihalotrialkylphophoranes, dihalotriphenylphosphoranes, oxalyl chloride and phosgene. Preferred are phosphorus oxyhalides and phosphorus pentahalides. To obtain complete conversion, at least 0.33 equivalents of phosphorus oxyhalide versus the compound of Formula 50 should be used (i.e. the mole ratio of phosphorus oxyhalide to the compound of Formula 50 is 0.33), preferably between about 0.33 and 1.2 equivalents. To obtain complete conversion, at least 0.20 equivalents of phosphorus pentahalide versus the compound of Formula 50 should be used, preferably between about 0.20 and 1.0 equivalents. Compounds of Formula 50 wherein R¹⁰ is C₁-C₄ alkyl are preferred for this reaction. Typical solvents for this halogenation include halogenated alkanes, such as dichloromethane, chloroform, chlorobutane and the like, aromatic solvents, such as benzene, xylene, chlorobenzene and the like, ethers, such as tetrahydrofuran, p-dioxane, diethyl ether, and the like, and polar aprotic solvents such as acetonitrile, N,N-dimethylformamide, and the like. Optionally, an organic base, such as triethylamine, pyridine, N,N-dimethylaniline or the like, can be added. Addition of a catalyst, such as N,N-diethylformamide, is also an option. Preferred is the process in which the solvent is acetonitrile and a base is absent. Typically, neither a base nor a catalyst is required when acetonitrile solvent is used. The preferred process is conducted by mixing the compound of Formula 50 in acetonitrile. The halogenating reagent is then added over a convenient time, and the mixture is then held at the desired temperature until the reaction is complete. The reaction temperature is typically between 20° C. and the boiling point of acetonitrile, and the reaction time is typically less than 2 hours. The reaction mass is then neutralized with an inorganic base, such as sodium bicarbonate, sodium hydroxide and the like, or an organic base, such as sodium acetate. The desired product, a compound of Formula 48, can be isolated by methods known to those skilled in the art, including crystallization, extraction and distillation.

Alternatively, compounds of Formula 48 wherein R⁹ is halogen such as Br or Cl can be prepared by treating the corresponding compounds of Formula 48 wherein R⁹ is a different halogen (e.g., Cl for making Formula 48 wherein R⁹ is Br) or a sulfonate group such as methanesulfonate, benzenesulfonate or p-toluenesulfonate with hydrogen bromide or hydrogen chloride, respectively. By this method the R⁹ halogen or sulfonate substituent on the Formula 48 starting compound is replaced with Br or Cl from hydrogen bromide or hydrogen chloride, respectively. The reaction is conducted in a suitable solvent such as dibromomethane, dichloromethane, acetic acid, ethyl acetate or acetonitrile. The reaction can be conducted at or near atmospheric pressure or above atmospheric pressure in a pressure vessel. The hydrogen halide starting material can be added in the form of a gas to the reaction mixture containing the Formula 48 starting compound and solvent. When R⁹ in the starting compound of Formula 48 is a halogen such as Cl, the reaction is preferably conducted in such a way that the hydrogen halide generated from the reaction is removed by sparging or other suitable means. Alternatively, the hydrogen halide starting material can be first dissolved in an inert solvent in which it is highly soluble (such as acetic acid) before contacting with the starting compound of Formula 48 either neat or in solution. Also when R⁹ in the starting compound of Formula 48 is a halogen such as Cl, substantially more than one equivalent of hydrogen halide starting material (e.g., 4 to 10 equivalents) is typically needed depending upon the level of conversion desired. One equivalent of hydrogen halide starting material can provide high conversion when R⁹ in the starting compound of Formula 48 is a sulfonate group, but when the starting compound of Formula 48 comprises at least one basic function (e.g., a nitrogen-containing heterocycle), more than one equivalent of hydrogen halide starting material is typically needed. The reaction can be conducted between about 0 and 100° C., most conveniently near ambient temperature (e.g., about 10 to 40° C.), and more preferably between about 20 and 30° C. Addition of a Lewis acid catalyst (such as aluminum tribromide for preparing Formula 48 wherein R⁹ is Br) can facilitate the reaction. The product of Formula 48 is isolated by the usual methods known to those skilled in the art, including extraction, distillation and crystallization.

Starting compounds of Formula 48 wherein R⁹ is Cl or Br can be prepared from corresponding compounds of Formula 50 as already described. Starting compounds of Formula 48 wherein R⁹ is a sulfonate group can likewise be prepared from corresponding compounds of Formula 50 by standard methods such as treatment with a sulfonyl chloride (e.g., methanesulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride) and base such as a tertiary amine (e.g., triethylamine) in a suitable solvent such as dichloromethane.

Pyrazolecarboxylic acids of Formula 2h wherein R⁹ is OCH₂CF₃ or Formula 2i wherein R⁹ is OCHF₂ can be prepared by the method outlined in Scheme 20. In this method, instead of being halogenated as shown in Scheme 19, the compound of Formula 50 is oxidized to the compound of Formula 51. The reaction conditions for this oxidation are as already described for the conversion of the compound of Formula 48 to the compound of Formula 49 in Scheme 18.

The compound of Formula 51 is then alkylated to form the compound of Formula 54 (R⁹ is OCH₂CF₃) by contact with an alkylating agent CF₃CH₂Lg (52) in the presence of a base. In the alkylating agent 52, Lg is a nucleophilic reaction leaving group such as halogen (e.g., Br, I), OS(O)₂CH₃ (methanesulfonate), OS(O)₂CF₃, OS(O)₂Ph-p-CH₃ (p-toluene-sulfonate), and the like; methanesulfonate works well. The reaction is conducted in the presence of at least one equivalent of a base. Suitable bases include inorganic bases, such as alkali metal (such as lithium, sodium or potassium) carbonates and hydroxides, and organic bases, such as triethylamine, diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction is generally conducted in a solvent, which can comprise alcohols, such as methanol and ethanol, halogenated alkanes, such as dichloromethane, aromatic solvents, such as benzene, toluene and chlorobenzene, ethers, such as tetrahydrofuran, and polar aprotic solvents, such as acetonitrile, N,N-dimethylformamide, and the like. Alcohols and polar aprotic solvents are preferred for use with inorganic bases. Potassium carbonate as base and acetonitrile as solvent are preferred. The reaction is typically conducted between about 0 and 150° C., and more typically between ambient temperature and 100° C.

wherein R¹⁰ is C₁-C₄ alkyl, and Lg is a leaving group.

The compound of Formula 51 can also be alkylated to form the compound of Formula 55 (R⁹ is OCHF₂) by contact with difluorocarbene, prepared from CHClF₂ (53) in the presence of a base. The reaction is generally conducted in a solvent, which can comprise ethers, such as tetrahydrofuran or dioxane, and polar aprotic solvents, such as acetonitrile, N,N-dimethylformamide, and the like. The base can be selected from inorganic bases such as potassium carbonate, sodium hydroxide or sodium hydride. Preferably the reaction is conducted using potassium carbonate with N,N-dimethylformamide as the solvent. The product of Formula 54 or 55 can be isolated by conventional techniques such as extraction. The esters can then be converted to the carboxylic acids of Formula 2h or 2i by the methods already described for the conversion of Formula 43 to Formula 2f in Scheme 16.

Compounds of Formula 50 can be prepared from compounds of Formula 44 (see Scheme 17) as outlined in Scheme 21.

wherein R¹⁰ is C₁-C₄ alkyl.

In this method, a hydrazine compound of Formula 44 is contacted with a compound of Formula 56 (a fumarate ester or maleate ester or a mixture thereof may be used) in the presence of a base and a solvent. The base is typically a metal alkoxide salt, such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, and the like. Greater than 0.5 equivalents of base versus the compound of Formula 56 should be used, preferably between 0.9 and 1.3 equivalents. Greater than 1.0 equivalents of the compound of Formula 44 should be used, preferably between 1.0 to 1.3 equivalents. Polar protic and polar aprotic organic solvents can be used, such as alcohols, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide and the like. Preferred solvents are alcohols such as methanol and ethanol. It is especially preferred that the alcohol be the same as that making up the fumarate or maleate ester and the alkoxide base. The reaction is typically conducted by mixing the compound of Formula 56 and the base in the solvent. The mixture can be heated or cooled to a desired temperature and the compound of Formula 44 added over a period of time. Typically reaction temperatures are between 0° C. and the boiling point of the solvent used. The reaction may be conducted under greater than atmospheric pressure in order to increase the boiling point of the solvent. Temperatures between about 30 and 90° C. are typically preferred. The addition time can be as quick as heat transfer allows. Typical addition times are between 1 minute and 2 hours. Optimum reaction temperature and addition time vary depending upon the identities of the compounds of Formula 44 and Formula 56. After addition, the reaction mixture can be held for a time at the reaction temperature. Depending upon the reaction temperature, the required hold time may be from 0 to 2 hours. Typical hold times are 10 to 60 minutes. The reaction mass then can be acidified by adding an organic acid, such as acetic acid and the like, or an inorganic acid, such as hydrochloric acid, sulfuric acid and the like. Depending on the reaction conditions and the means of isolation, the —CO₂R¹⁰ function on the compound of Formula 50 may be hydrolyzed to —CO₂H; for example, the presence of water in the reaction mixture can promote such hydrolysis. If the carboxylic acid (—CO₂H) is formed, it can be converted back to —CO₂R¹⁰ wherein R¹⁰ is C₁-C₄ alkyl using esterification methods well known in the art. The desired product, a compound of Formula 50, can be isolated by methods known to those skilled in the art, such as crystallization, extraction or distillation.

The synthesis of representative pyrazole acids of Formula 2j is depicted in Scheme 22. Reaction of a dimethylaminoylidene ketoester of Formula 58 with substituted hydrazines of Formula 31 affords the pyrazoles of Formula 59. Substituent groups R^(a) and R^(b) include, for example, alkyl, haloalkyl, and optionally substituted aromatic and heteroaromatic rings. Notable R^(a) substituents include alkyl and haloalkyl, with 2,2,2-trifluoroethyl especially noteworthy, and R^(b) substituents include optionally substituted phenyl or pyridine. The esters of Formula 59 are converted to the acids of Formula 2j by standard hydrolysis methods.

The synthesis of pyrazole acids of Formula 2k, a subset of the pyrazole acids of Formula 2j wherein R^(b) is a substituted 2-pyridyl moiety attached to the 5-position of the pyrazole ring, is depicted in Scheme 23. This synthesis is conducted according to the general synthesis described in Scheme 22. Notable R^(c) substituents include hydrogen and halogen.

The synthesis of representative pyrazole acids of Formula 2m, as well as an alternative synthesis of Formula 2j, is depicted in Scheme 24. Reaction of the dimethylaminoylidene ketoester of Formula 58 with hydrazine affords the pyrazole of Formula 63. Reaction of the pyrazole 63 with alkylating agents of Formula 23 (R^(a)-Lg wherein Lg is a leaving group such as halogen (e.g., Br, I), OS(O)₂CH₃ (methanesulfonate), OS(O)₂CF₃, OS(O)₂Ph-p-CH₃ (p-toluenesulfonate), and the like) affords a mixture of pyrazoles of Formulae 64 and 65. This mixture of pyrazole isomers is readily separated by chromatographic methods and converted to the corresponding acids 2m and 2j. Substituent groups R^(a) and R^(b) include, for example, alkyl, haloalkyl, and optionally substituted aromatic and heteroaromatic rings. Noteworthy R^(a) substituents include alkyl and haloalkyl groups and R^(b) substituents include optionally substituted phenyl or pyridine.

Of note is the synthesis of pyridinylpyrazole acids of Formula 2n, a subset of the acids of Formula 2m wherein R^(b) is a substituted 2-pyridinyl and attached to the 3-position of the pyrazole ring, as well as an alternative synthesis of Formula 2k, is depicted in Scheme 25. In Formula 2n and 2k the substituent R^(c) is, for example, R⁷ and is notably hydrogen and halogen. This synthesis is conducted according to the general synthesis described in Scheme 24.

A general synthesis of pyrrole acids of Formula 2o is depicted in Scheme 26. Substituent groups R^(a) include, for example, alkyl, haloalkyl, and optionally substituted aromatic and heteroaromatic rings. Treatment of a compound of Formula 69 with 2,5-dimethoxytetrahydrofuran (70) affords a pyrrole of Formula 71. Formylation of the pyrrole 71 to provide the aldehyde of Formula 72 can be accomplished by using standard Vilsmeier-Haack formulation conditions, such as N,N-dimethylformamide (DMF) and phosphorus oxychloride. Halogenation of the compound of Formula 72 with N-halosuccinimides (NXS) such as N-chlorosuccinimide or N-bromosuccinimide occurs preferentially at the 4-position of the pyrrole ring. Oxidation of the halogenated aldehyde affords the pyrrole acid of Formula 2o. The oxidation can be accomplished by using a variety of standard oxidation conditions.

The synthesis of certain pyridinylpyrrole acids of Formula 2p is depicted in Scheme 27. The compound of Formula 74, 3-chloro-2-aminopyridine, is a known compound (see J. Heterocycl. Chem. 1987, 24(5), 1313-16). A convenient preparation of 74 from the 2-aminopyridine of Formula 73 involves protection, ortho-metallation, chlorination and subsequent deprotection. The remaining synthesis is conducted according to the general synthesis described in Scheme 26.

It is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. ¹H NMR spectra are reported in ppm downfield from tetramethylsilane; “s” means singlet, “d” means doublet, “t” means triplet, “q” means quartet, “m” means multiplet, “dd” means doublet of doublets, “dt” means doublet of triplets, and “br s” means broad singlet. Quantitative HPLC of the product was performed using an Ace C18 or C4 Ultra Inert® chromatography column (reversed phase column manufactured by MacMod Analytical Inc., Chadds Ford, Pa. 19317) (3 μm particle size, 4.6 mm×15 cm, eluent 5-80% acetonitrile/pH 3 phosphate buffer).

EXAMPLE 1 Preparation of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one

To a solution of methanesulfonyl chloride (5.0 mL, 7.4 g, 65 mmol) in acetonitrile (55 mL) at −5° C. was added dropwise a solution of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see WO 03/015519 for preparation) (93.6% purity, 16.16 g, 50.0 mmol) and 3-picoline (8.3 mL, 7.9 g, 85 mmol) in acetonitrile (50 mL) over five minutes while maintaining the temperature at about −5 to 0° C. A slurry formed during the addition. The mixture was stirred for 5 minutes at this temperature, and then 6-chloro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (99.0% purity, 11.22 g, 52.5 mmol) was added all at once, and the residue was rinsed with acetonitrile (10 mL). To the reaction mixture was added 3-picoline (8.3 mL, 7.9 g, 85 mmol) dropwise in 5 minutes at −5 to 0° C. After stirring for 15 minutes at −5 to 0° C., the reaction mixture was heated to 50° C. and stirred 4 hours. Then the reaction mixture was cooled to room temperature, water (30 mL) was added dropwise and the mixture was stirred 15 minutes. The mixture was filtered, and the solids were re-slurried sequentially with 4:1 acetonitrile-water (2×40 mL) and acetonitrile (3×40 mL), and then dried under nitrogen to afford the title product as a light yellow powder, 20.95 g (93.6% purity by HPLC, 86.7% yield calculated based on the purity).

¹H NMR (DMSO-d₆) δ 1.72 (s, 3H) 7.52 (s, 1H), 7.74-7.80 (m, 2H), 7.89 (m, 1H), 8.34 (dd, 1H, J=8.4, 0.9 Hz), 8.62 (dd, 1H, J=4.5, 0.9 Hz).

EXAMPLE 2 Preparation of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one by inverse addition

To a mixture of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see WO 03/015519 for preparation) (93.6% purity, 16.16 g, 50.0 mmol), 6-chloro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (99.0% purity, 11.22 g, 52.5 mmol), and 3-picoline (16.5 mL, 15.8 g, 170 mmol) in acetonitrile (65 mL) at about −5° C. was added dropwise methanesulfonyl chloride (5.0 mL, 7.4 g, 65 mmol) in acetonitrile (15 mL). After 15 minutes at −5 to 0° C., the reaction mixture was heated to 50° C. for 4 hours. The reaction mixture was then cooled to room temperature, water (20 mL) was added dropwise, and the reaction mixture was stirred 15 minutes. The mixture was filtered, and the solids were washed sequentially with 4:1 acetonitrile-water (2×35 mL) and acetonitrile (3×35 mL), and dried under nitrogen to afford the title product as a light yellow powder, 20.55 g (94.4% purity by HPLC, 85.8% yield calculated based on the purity).

EXAMPLE 3 Preparation of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one by inverse addition

A mixture of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (97.9% purity, 3.09 g, 10.0 mmol), 6-cyano-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (96.3% purity, 2.10 g, 10.0 mmol) and 3-picoline (3.30 mL, 3.16 g, 34 mmol) in acetonitrlle (65 mL) was cooled to about −5° C. Then methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) in acetonitrile (3 mL) was added dropwise at −5 to 0° C. After 15 minutes at −5 to 0° C., the reaction mixture was heated to 50° C. for 4 hours. The reaction mixture was then cooled to room temperature, water (4 mL) was added dropwise, and the reaction mixture was stirred 15 minutes. The mixture was filtered, and the solids were washed sequentially with 4:1 acetonitrile-water (2×2 mL) and acetonitrile (3×2 mL), and dried under nitrogen to afford the title product as a pale green powder, 3.71 g (94.2% purity by HPLC, 82.0% yield calculated based on the purity), melting at 263-267° C.

¹H NMR (DMSO-d₆) δ 1.73 (s, 3H) 7.59 (s, 1H), 7.77 (dd, 1H, J=8.2, 4.6 Hz), 8.09 (m, 1H), 8.32-8.40 (m, 2H), 8.63 (dd, 1H, J=4.8, 1.5 Hz).

EXAMPLE 4 Preparation of 3-bromo-N-[4-chloro-2-methyl-6-[(1-methylamino)carbonyl]-phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide in one pot

To a mixture of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see WO 03/015519 for preparation) (93.6% purity, 16.16 g, 50.0 mmol), 6-chloro-8-methyl-1H-benzo[d][1,3]oxazine-2,4dione (99.0% purity, 11.22 g, 52.5 mmol), and 3-picoline (16.5 mL, 15.8 g, 170 mmol) in acetonitrile (65 mL) at −5° C. was added dropwise methanesulfonyl chloride (5.0 mL, 7.4 g, 65 mmol) in acetonitrile (15 mL). After stirring 15 minutes at −5 to 0° C., the mixture was heated to 50° C. for 4 hours. The reaction mixture was then cooled to room temperature, water (29 mL) was added dropwise, and the reaction mixture was stirred 15 minutes. Then 40% aqueous methylamine (20.0 mL, 17.9 g, 231 mmol) was added all at once, and the reaction mixture was stirred overnight at room temperature. The mixture was filtered, and the solids were washed sequentially with 2:1 acetonitrile-water (2×30 mL) and acetonitrile (3×30 mL), and dried under nitrogen to afford the title product as a light yellow powder, 22.44 g (95.5% purity by BPLC, 88.7% yield calculated based on the purity).

¹H NMR (CDCl₃) δ 2.18 (s, 3H), 2.95 (s, 3H), 6.21 (m, 1H), 7.10 (s, 1H), 7.24 (m, 2H), 7.39 (m, 1H), 7.80 (d, 1H), 8.45 (d, 1H).

By the methods and procedures described herein together with methods known in the art, the following compounds of Table 1 can be prepared.

TABLE 1

R⁴ R⁵ R⁹ R⁷ CH₃ F CF₃ Cl CH₃ F CF₃ Br CH₃ F Cl Cl CH₃ F Cl Br CH₃ F Br Cl CH₃ F Br Br CH₃ Cl CF₃ Cl CH₃ Cl CF₃ Br CH₃ Cl Cl Cl CH₃ Cl Cl Br CH₃ Cl Br Cl CH₃ Cl Br Br CH₃ Br CF₃ Cl CH₃ Br CF₃ Br CH₃ Br Cl Cl CH₃ Br Cl Br CH₃ Br Br Cl CH₃ Br Br Br CH₃ I CF₃ Cl CH₃ I CF₃ Br CH₃ I Cl Cl CH₃ I Cl Br CH₃ I Br Cl CH₃ I Br Br CH₃ CF₃ CF₃ Cl CH₃ CF₃ CF₃ Br CH₃ CF₃ Cl Cl CH₃ CF₃ Cl Br CH₃ CF₃ Br Cl CH₃ CF₃ Br Br CH₃ Cl Cl Cl F F CF₃ Cl F F CF₃ Br F F Cl Cl F F Cl Br F F Br Cl F F Br Br F Cl CF₃ Cl F Cl CF₃ Br F Cl Cl Cl F Cl Cl Br F Cl Br Cl F Cl Br Br F Br CF₃ Cl F Br CF₃ Br F Br Cl Cl F Br Cl Br F Br Br Cl F Br Br Br F I CF₃ Cl F I CF₃ Br F I Cl Cl F I Cl Br F I Br Cl F I Br Br F CF₃ CF₃ Cl F CF₃ CF₃ Br F CF₃ Cl Cl F CF₃ Cl Br F CF₃ Br Cl F CF₃ Br Br F F OCHF₂ Cl F F OCHF₂ Br F Cl OCHF₂ Cl F Cl OCHF₂ Br F I OCHF₂ Cl F I OCHF₂ Br CH₃ CN CF₃ Cl CH₃ CN CF₃ Br CH₃ CN Cl Cl CH₃ CN Cl Br CH₃ CN Br Cl CH₃ CN Br Br CH₃ CN OCH₂CF₃ Cl CH₃ CN OCH₂CF₃ Br CH₃ CN OCHF₂ Cl CH₃ CN OCHF₂ Br F CN CF₃ Cl F CN CF₃ Br F CN Br Cl F CN Br Br Cl F CF₃ Cl Cl F CF₃ Br Cl F Cl Cl Cl F Cl Br Cl F Br Cl Cl F Br Br Cl Cl CF₃ Cl Cl Cl CF₃ Br Cl Cl Cl Cl Cl Cl Cl Br Cl Cl Br Cl Cl Cl Br Br Cl Br CF₃ Cl Cl Br CF₃ Br Cl Br Cl Cl Cl Br Cl Br Cl Br Br Cl Cl Br Br Br Cl I CF₃ Cl Cl I CF₃ Br Cl I Cl Cl Cl I Cl Br Cl I Br Cl Cl I Br Br Cl CF₃ CF₃ Cl Cl CF₃ CF₃ Br Cl CF₃ Cl Cl Cl CF₃ Cl Br Cl CF₃ Br Cl Cl CF₃ Br Br Cl Cl Cl Cl Br F CF₃ Cl Br F CF₃ Br Br F Cl Cl Br F Cl Br Br F Br Cl Br F Br Br Br Cl CF₃ Cl Br Cl CF₃ Br Br Cl Cl Cl Br Cl Cl Br Br Cl Br Cl Br Cl Br Br Br Br CF₃ Cl Br Br CF₃ Br Br Br Cl Cl Br Br Cl Br Br Br Br Cl Br Br Br Br Br I CF₃ Cl Br I CF₃ Br Br I Cl Cl Br I Cl Br Br I Br Cl Br I Br Br Br CF₃ CF₃ Cl Br CF₃ CF₃ Br Br CF₃ Cl Cl Br CF₃ Cl Br Br CF₃ Br Cl Br CF₃ Br Br Br F OCHF₂ Cl Br F OCHF₂ Br Br Cl OCHF₂ Cl Br Cl OCHF₂ Br Br Br OCHF₂ Cl Br Br OCHF₂ Br Cl CN CF₃ Cl Cl CN CF₃ Br Cl CN Cl Cl Cl CN Cl Br Cl CN Br Cl Cl CN Br Br Cl CN OCH₂CF₃ Cl Cl CN OCH₂CF₃ Br Cl CN OCHF₂ Cl Cl CN OCHF₂ Br F CN Cl Cl F CN Cl Br F CN OCHF₂ Cl F CN OCHF₂ Br CH₃ F OCH₂CF₃ Cl CH₃ F OCH₂CF₃ Br CH₃ F OCHF₂ Cl CH₃ F OCHF₂ Br Cl F OCH₂CF₃ Cl Cl F OCH₂CF₃ Br Cl F OCHF₂ Cl Cl F OCHF₂ Br CH₃ Cl OCH₂CF₃ Cl CH₃ Cl OCH₂CF₃ Br CH₃ Cl OCHF₂ Cl CH₃ Cl OCHF₂ Br Cl Cl OCH₂CF₃ Cl Cl Cl OCH₂CF₃ Br Cl Cl OCHF₂ Cl Cl Cl OCHF₂ Br CH₃ Br OCH₂CF₃ Cl CH₃ Br OCH₂CF₃ Br CH₃ Br OCHF₂ Cl CH₃ Br OCHF₂ Br Cl Br OCH₂CF₃ Cl Cl Br OCH₂CF₃ Br Cl Br OCHF₂ Cl Cl Br OCHF₂ Br Cl I OCH₂CF₃ Cl Cl I OCH₂CF₃ Br Cl I OCHF₂ Cl Cl I OCHF₂ Br CH₃ I OCH₂CF₃ Cl CH₃ I OCH₂CF₃ Br CH₃ I OCHF₂ Cl CH₃ I OCHF₂ Br Cl CF₃ OCH₂CF₃ Cl Cl CF₃ OCH₂CF₃ Br Cl CF₃ OCHF₂ Cl Cl CF₃ OCHF₂ Br CH₃ CF₃ OCH₂CF₃ Cl CH₃ CF₃ OCH₂CF₃ Br CH₃ CF₃ OCHF₂ Cl CH₃ CF₃ OCHF₂ Br Br F OCH₂CF₃ Cl Br F OCH₂CF₃ Br F F OCH₂CF₃ Cl F F OCH₂CF₃ Br Br Cl OCH₂CF₃ Cl Br Cl OCH₂CF₃ Br F Cl OCH₂CF₃ Cl F Cl OCH₂CF₃ Br Br Br OCH₂CF₃ Cl Br Br OCH₂CF₃ Br F Br OCH₂CF₃ Cl F Br OCH₂CF₃ Br F Br OCHF₂ Cl F Br OCHF₂ Br Br I OCH₂CF₃ Cl Br I OCH₂CF₃ Br Br I OCHF₂ Cl Br I OCHF₂ Br F I OCH₂CF₃ Cl F I OCH₂CF₃ Br Br CF₃ OCH₂CF₃ Cl Br CF₃ OCH₂CF₃ Br Br CF₃ OCHF₂ Cl Br CF₃ OCHF₂ Br F CF₃ OCH₂CF₃ Cl F CF₃ OCH₂CF₃ Br F CF₃ OCHF₂ Cl F CF₃ OCHF₂ Br Br CN CF₃ Cl Br CN CF₃ Br Br CN Cl Cl Br CN Cl Br Br CN Br Cl Br CN Br Br Br CN OCHF₂ Cl Br CN OCHF₂ Br Br CN OCH₂CF₃ Cl Br CN OCH₂CF₃ Br F CN OCH₂CF₃ Cl F CN OCH₂CF₃ Br

The fused oxazinone preparation method of the present invention can be used to prepare a wide variety of compounds of Formula 1 that are useful as intermediates for the preparation of crop protection agents, pharmaceuticals and other fine chemicals. Exhibit 4 lists examples of fused oxazinones which can be prepared according to the method of the present invention from corresponding carboxylic acids of Formula 2 and isatoic anhydrides of Formula 5, including fused oxazinones which are useful in the preparation of products having antiviral, nematocidal, microbiocidal, acaricidal, fungicidal and herbicidal utility. These examples are to be construed as illustrative, but not limiting, of the diverse scope of applicability of the method of the present invention. Other compounds preparable according to the method of the present invention may be useful for preparation of pharmaceutical products having additional utilities, such as anti-tumor activity, anti-allergenic activity, protease inhibition, etc.

Furthermore as shown in Scheme A, compounds of Formula 1 can be used to prepare compounds of Formula II by reaction with nucleophiles, optionally in the presence of additional base.

As shown in Scheme 28, reaction of Formula 1 with nucleophiles of Formula 77 wherein R^(d) can be an optionally substituted carbon moiety (i.e. alcohols) leads to esters of Formula IIa. Reaction of Formula 1 with nucleophiles of Formula 78 wherein R^(e) and R^(f) can be independently H or an optionally substituted carbon moiety (i.e. ammonia, primary amines or secondary amines) leads to amides of Formula IIb.

Typical procedures for preparation of compounds of Formula IIb involve combination of an amine of Formula 78 with the fused oxazinone of Formula 1. The reaction can be run neat or in a variety of suitable solvents including acetonitrile, tetrahydrofuran, diethyl ether, dichloromethane or chloroform with optimum temperatures ranging from room temperature to the reflux temperature of the solvent. For references to the chemistry of heterocyclic fused oxazinones see Jakobsen et al., Biorganic and Medicinal Chemistry 2000, 8, 2803-2812 and references cited therein.

As a particular example, compounds of Formula 1a are useful for preparing compounds of Formula III

wherein

-   -   X is N or CR⁶;     -   Y is N or CH;     -   R¹ is H;     -   R² is H or CH₃;     -   R³ is C₁-C₆ alkyl;     -   R⁴ is C₁-C₄ alkyl or halogen;     -   R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, CN or halogen;     -   R⁶ and R⁷ are independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl,         halogen, CN or C₁-C₄ haloalkoxy;     -   R⁸ is H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆         cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl, C₂-C₄         haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂, C₁-C₄         alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,         C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆         cycloalkylamino, (C₁-C₄ alkyl)(C₃-C₆ cycloalkyl)amino, C₂-C₄         alkylcarbonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl,         C₃-C₈ dialkylaminocarbonyl or C₃-C₆ trialkylsilyl;     -   R⁹ is CF₃, OCF₃, OCHF₂, OCH₂CF₃, S(O)_(p)CF₃, S(O)_(p)CHF₂ or         halogen; and     -   p is 0, 1 or 2.

Compounds of Formula III are useful as insecticides, as described, for example, in PCT Publication No. WO 01/70671, published Sep. 27, 2001, as well as in U.S. Patent Application 60/324,173, filed Sep. 21, 2001, U.S. Patent Application 60/323,941, filed Sep. 21, 2001 and U.S. Patent Application 60/369,661, filed Apr. 2, 2002. The preparation of compounds of Formula 1a and Formula III is described in U.S. Patent Application 60/400356, filed Jul. 31, 2002, and U.S. Patent Application 60/446451, filed Feb. 11, 2003 and hereby incorporated herein in their entirety by reference; as well as in U.S. Patent Application 60/369,659, filed Apr. 2, 2002 and U.S. Patent Application 60/369,660, filed Apr. 2, 2002.

Compounds of Formula III can be prepared by the reaction of benzoxazinones of Formula 1a with C₁-C₆ alkylamines and (C₁-C₆ alkyl)(methyl)amines of Formula 79 as outlined in Scheme 29.

The reaction can be run neat or in a variety of suitable solvents including acetonitrile, tetrahydrofuran, diethyl ether, dichloromethane or chloroform with optimum temperatures ranging from room temperature to the reflux temperature of the solvent. The general reaction of benzoxazinones with amines to produce anthranilamides is well documented in the chemical literature. For a review of benzoxazinone chemistry see Jakobsen et al., Biorganic and Medicinal Chemistry 2000, 8, 2095-2103 and references cited within. See also Coppola, J. Heterocyclic Chemistry 1999, 36, 563-588.

Of note are methods for preparing compounds of Formula 1a or Formula III wherein R⁹ is CF₃, OCF₃, OCHF₂, OCH₂CF₃ or halogen. Of particular note are methods for preparing compounds of Formula 1a or Formula III wherein R⁹ is CF₃, OCHF₂, OCH₂CF₃, Cl or Br. Preferred are methods for preparing compounds of Formula 1a or Formula III wherein

-   -   X is N;     -   Y is N;     -   R² is H or CH₃;     -   R³ is C₁-C₄ alkyl;     -   R⁴is CH₃, F, Cl or Br,     -   R⁵is CF₃, CN, F, Cl, Br or I;     -   R⁷ is Cl or Br;     -   R⁸ is H, and     -   R⁹ is CF₃, OCHF₂, OCH₂CF₃, Cl or Br.

Also of particular note are compounds of Formula III wherein R⁹ is OCHF₂.

By the procedures described herein together with methods known in the art, the following compounds of Table 2 can be prepared. The following abbreviations are used in the Tables which follow: t means tertiary, s means secondary, n means normal, i means iso, Me means methyl, Et means ethyl, Pr means propyl, i-Pr means isopropyl, and Bu means butyl.

TABLE 2

R⁴ R⁵ R⁹ R³ R² R⁷ CH₃ F CF₃ Me H Cl CH₃ F CF₃ Et H Cl CH₃ F CF₃ i-Pr H Cl CH₃ F CF₃ t-Bu H Cl CH₃ F CF₃ Me Me Cl CH₃ F CF₃ Me H Br CH₃ F CF₃ Et H Br CH₃ F CF₃ i-Pr H Br CH₃ F CF₃ t-Bu H Br CH₃ F CF₃ Me Me Br CH₃ F Cl Me H Cl CH₃ F Cl Et H Cl CH₃ F Cl i-Pr H Cl CH₃ F Cl t-Bu H Cl CH₃ F Cl Me Me Cl CH₃ F Cl Me H Br CH₃ F Cl Et H Br CH₃ F Cl i-Pr H Br CH₃ F Cl t-Bu H Br CH₃ F Cl Me Me Br CH₃ F Br Me H Cl CH₃ F Br Et H Cl CH₃ F Br i-Pr H Cl CH₃ F Br t-Bu H Cl CH₃ F Br Me Me Cl CH₃ F Br Me H Br CH₃ F Br Et H Br CH₃ F Br i-Pr H Br CH₃ F Br t-Bu H Br CH₃ F Br Me Me Br CH₃ F OCH₂CF₃ Me H Cl CH₃ F OCH₂CF₃ Et H Cl CH₃ F OCH₂CF₃ i-Pr H Cl CH₃ F OCH₂CF₃ t-Bu H Cl CH₃ F OCH₂CF₃ Me Me Cl CH₃ F OCH₂CF₃ Me H Br CH₃ F OCH₂CF₃ Et H Br CH₃ F OCH₂CF₃ i-Pr H Br CH₃ F OCH₂CF₃ t-Bu H Br CH₃ F OCH₂CF₃ Me Me Br CH₃ Cl CF₃ Me H Cl CH₃ Cl CF₃ Et H Cl CH₃ Cl CF₃ i-Pr H Cl CH₃ Cl CF₃ t-Bu H Cl CH₃ Cl CF₃ Me Me Cl CH₃ Cl CF₃ Me H Br CH₃ Cl CF₃ Et H Br CH₃ Cl CF₃ i-Pr H Br CH₃ Cl CF₃ t-Bu H Br CH₃ Cl CF₃ Me Me Br CH₃ Cl Cl Me H Cl CH₃ Cl Cl Et H Cl CH₃ Cl Cl i-Pr H Cl CH₃ Cl Cl t-Bu H Cl CH₃ Cl Cl Me Me Cl CH₃ Cl Cl Me H Br CH₃ Cl Cl Et H Br CH₃ Cl Cl i-Pr H Br CH₃ Cl Cl t-Bu H Br CH₃ Cl Cl Me Me Br CH₃ Cl Br Me H Cl CH₃ Cl Br Et H Cl CH₃ Cl Br i-Pr H Cl CH₃ Cl Br t-Bu H Cl CH₃ Cl Br Me Me Cl CH₃ Cl Br Me H Br CH₃ Cl Br Et H Br CH₃ Cl Br i-Pr H Br CH₃ Cl Br t-Bu H Br CH₃ Cl Br Me Me Br CH₃ Cl OCH₂CF₃ Me H Cl CH₃ Cl OCH₂CF₃ Et H Cl CH₃ Cl OCH₂CF₃ i-Pr H Cl CH₃ Cl OCH₂CF₃ t-Bu H Cl CH₃ Cl OCH₂CF₃ Me Me Cl CH₃ Cl OCH₂CF₃ Me H Br CH₃ Cl OCH₂CF₃ Et H Br CH₃ Cl OCH₂CF₃ i-Pr H Br CH₃ Cl OCH₂CF₃ t-Bu H Br CH₃ Cl OCH₂CF₃ Me Me Br CH₃ Br CF₃ Me H Cl CH₃ Br CF₃ Et H Cl CH₃ Br CF₃ i-Pr H Cl CH₃ Br CF₃ t-Bu H Cl CH₃ Br CF₃ Me Me Cl CH₃ Br CF₃ Me H Br CH₃ Br CF₃ Et H Br CH₃ Br CF₃ i-Pr H Br CH₃ Br CF₃ t-Bu H Br CH₃ Br CF₃ Me Me Br CH₃ Br Cl Me H Cl CH₃ Br Cl Et H Cl CH₃ Br Cl i-Pr H Cl CH₃ Br Cl t-Bu H Cl CH₃ Br Cl Me Me Cl CH₃ Br Cl Me H Br CH₃ Br Cl Et H Br CH₃ Br Cl i-Pr H Br CH₃ Br Cl t-Bu H Br CH₃ Br Cl Me Me Br CH₃ Br Br Me H Cl CH₃ Br Br Et H Cl CH₃ Br Br i-Pr H Cl CH₃ Br Br t-Bu H Cl CH₃ Br Br Me Me Cl CH₃ Br Br Me H Br CH₃ Br Br Et H Br CH₃ Br Br i-Pr H Br CH₃ Br Br t-Bu H Br CH₃ Br Br Me Me Br CH₃ Br OCH₂CF₃ Me H Cl CH₃ Br OCH₂CF₃ Et H Cl CH₃ Br OCH₂CF₃ i-Pr H Cl CH₃ Br OCH₂CF₃ t-Bu H Cl CH₃ Br OCH₂CF₃ Me Me Cl CH₃ Br OCH₂CF₃ Me H Br CH₃ Br OCH₂CF₃ Et H Br CH₃ Br OCH₂CF₃ i-Pr H Br CH₃ Br OCH₂CF₃ t-Bu H Br CH₃ Br OCH₂CF₃ Me Me Br CH₃ I CF₃ Me H Cl CH₃ I CF₃ Et H Cl CH₃ I CF₃ i-Pr H Cl CH₃ I CF₃ t-Bu H Cl CH₃ I CF₃ Me Me Cl CH₃ I CF₃ Me H Br CH₃ I CF₃ Et H Br CH₃ I CF₃ i-Pr H Br CH₃ I CF₃ t-Bu H Br CH₃ I CF₃ Me Me Br CH₃ I Cl Me H Cl CH₃ I Cl Et H Cl CH₃ I Cl i-Pr H Cl CH₃ I Cl t-Bu H Cl CH₃ I Cl Me Me Cl CH₃ I Cl Me H Br CH₃ I Cl Et H Br CH₃ I Cl i-Pr H Br CH₃ I Cl t-Bu H Br CH₃ I Cl Me Me Br CH₃ I Br Me H Cl CH₃ I Br Et H Cl CH₃ I Br i-Pr H Cl CH₃ I Br t-Bu H Cl CH₃ I Br Me Me Cl CH₃ I Br Me H Br CH₃ I Br Et H Br CH₃ I Br i-Pr H Br CH₃ I Br t-Bu H Br CH₃ I Br Me Me Br CH₃ I OCH₂CF₃ Me H Cl CH₃ I OCH₂CF₃ Et H Cl CH₃ I OCH₂CF₃ i-Pr H Cl CH₃ I OCH₂CF₃ t-Bu H Cl CH₃ I OCH₂CF₃ Me Me Cl CH₃ I OCH₂CF₃ Me H Br CH₃ I OCH₂CF₃ Et H Br CH₃ I OCH₂CF₃ i-Pr H Br CH₃ I OCH₂CF₃ t-Bu H Br CH₃ I OCH₂CF₃ Me Me Br CH₃ CF₃ CF₃ Me H Cl CH₃ CF₃ CF₃ Et H Cl CH₃ CF₃ CF₃ i-Pr H Cl CH₃ CF₃ CF₃ t-Bu H Cl CH₃ CF₃ CF₃ Me Me Cl CH₃ CF₃ CF₃ Me H Br CH₃ CF₃ CF₃ Et H Br CH₃ CF₃ CF₃ i-Pr H Br CH₃ CF₃ CF₃ t-Bu H Br CH₃ CF₃ CF₃ Me Me Br CH₃ CF₃ Cl Me H Cl CH₃ CF₃ Cl Et H Cl CH₃ CF₃ Cl i-Pr H Cl CH₃ CF₃ Cl t-Bu H Cl CH₃ CF₃ Cl Me Me Cl CH₃ CF₃ Cl Me H Br CH₃ CF₃ Cl Et H Br CH₃ CF₃ Cl i-Pr H Br CH₃ CF₃ Cl t-Bu H Br CH₃ CF₃ Cl Me Me Br CH₃ CF₃ Br Me H Cl CH₃ CF₃ Br Et H Cl CH₃ CF₃ Br i-Pr H Cl CH₃ CF₃ Br t-Bu H Cl CH₃ CF₃ Br Me Me Cl CH₃ CF₃ Br Me H Br CH₃ CF₃ Br Et H Br CH₃ CF₃ Br i-Pr H Br CH₃ CF₃ Br t-Bu H Br CH₃ CF₃ Br Me Me Br CH₃ CF₃ OCH₂CF₃ Me H Cl CH₃ CF₃ OCH₂CF₃ Et H Cl CH₃ CF₃ OCH₂CF₃ i-Pr H Cl CH₃ CF₃ OCH₂CF₃ t-Bu H Cl CH₃ CF₃ OCH₂CF₃ Me Me Cl CH₃ CF₃ OCH₂CF₃ Me H Br CH₃ CF₃ OCH₂CF₃ Et H Br CH₃ CF₃ OCH₂CF₃ i-Pr H Br CH₃ CF₃ OCH₂CF₃ t-Bu H Br CH₃ CF₃ OCH₂CF₃ Me Me Br CH₃ Cl Cl n-Pr H Cl CH₃ Cl Cl n-Bu H Cl CH₃ Cl Cl s-Bu H Cl CH₃ Cl Cl i-Bu H Cl CH₃ Cl Cl Et Me Cl F F CF₃ Me H Cl F F CF₃ Et H Cl F F CF₃ i-Pr H Cl F F CF₃ t-Bu H Cl F F CF₃ Me Me Cl F F CF₃ Me H Br F F CF₃ Et H Br F F CF₃ i-Pr H Br F F CF₃ t-Bu H Br F F CF₃ Me Me Br F F Cl Me H Cl F F Cl Et H Cl F F Cl i-Pr H Cl F F Cl t-Bu H Cl F F Cl Me Me Cl F F Cl Me H Br F F Cl Et H Br F F Cl i-Pr H Br F F Cl t-Bu H Br F F Cl Me Me Br F F Br Me H Cl F F Br Et H Cl F F Br i-Pr H Cl F F Br t-Bu H Cl F F Br Me Me Cl F F Br Me H Br F F Br Et H Br F F Br i-Pr H Br F F Br t-Bu H Br F F Br Me Me Br F F OCH₂CF₃ Me H Cl F F OCH₂CF₃ Et H Cl F F OCH₂CF₃ i-Pr H Cl F F OCH₂CF₃ t-Bu H Cl F F OCH₂CF₃ Me Me Cl F F OCH₂CF₃ Me H Br F F OCH₂CF₃ Et H Br F F OCH₂CF₃ i-Pr H Br F F OCH₂CF₃ t-Bu H Br F F OCH₂CF₃ Me Me Br F Cl CF₃ Me H Cl F Cl CF₃ Et H Cl F Cl CF₃ i-Pr H Cl F Cl CF₃ t-Bu H Cl F Cl CF₃ Me Me Cl F Cl CF₃ Me H Br F Cl CF₃ Et H Br F Cl CF₃ i-Pr H Br F Cl CF₃ t-Bu H Br F Cl CF₃ Me Me Br F Cl Cl Me H Cl F Cl Cl Et H Cl F Cl Cl i-Pr H Cl F Cl Cl t-Bu H Cl F Cl Cl Me Me Cl F Cl Cl Me H Br F Cl Cl Et H Br F Cl Cl i-Pr H Br F Cl Cl t-Bu H Br F Cl Cl Me Me Br F Cl Br Me H Cl F Cl Br Et H Cl F Cl Br i-Pr H Cl F Cl Br t-Bu H Cl F Cl Br Me Me Cl F Cl Br Me H Br F Cl Br Et H Br F Cl Br i-Pr H Br F Cl Br t-Bu H Br F Cl Br Me Me Br F Cl OCH₂CF₃ Me H Cl F Cl OCH₂CF₃ Et H Cl F Cl OCH₂CF₃ i-Pr H Cl F Cl OCH₂CF₃ t-Bu H Cl F Cl OCH₂CF₃ Me Me Cl F Cl OCH₂CF₃ Me H Br F Cl OCH₂CF₃ Et H Br F Cl OCH₂CF₃ i-Pr H Br F Cl OCH₂CF₃ t-Bu H Br F Cl OCH₂CF₃ Me Me Br F Br CF₃ Me H Cl F Br CF₃ Et H Cl F Br CF₃ i-Pr H Cl F Br CF₃ t-Bu H Cl F Br CF₃ Me Me Cl F Br CF₃ Me H Br F Br CF₃ Et H Br F Br CF₃ i-Pr H Br F Br CF₃ t-Bu H Br F Br CF₃ Me Me Br F Br Cl Me H Cl F Br Cl Et H Cl F Br Cl i-Pr H Cl F Br Cl t-Bu H Cl F Br Cl Me Me Cl F Br Cl Me H Br F Br Cl Et H Br F Br Cl i-Pr H Br F Br Cl t-Bu H Br F Br Cl Me Me Br F Br Br Me H Cl F Br Br Et H Cl F Br Br i-Pr H Cl F Br Br t-Bu H Cl F Br Br Me Me Cl F Br Br Me H Br F Br Br Et H Br F Br Br i-Pr H Br F Br Br t-Bu H Br F Br Br Me Me Br F Br OCH₂CF₃ Me H Cl F Br OCH₂CF₃ Et H Cl F Br OCH₂CF₃ i-Pr H Cl F Br OCH₂CF₃ t-Bu H Cl F Br OCH₂CF₃ Me Me Cl F Br OCH₂CF₃ Me H Br F Br OCH₂CF₃ Et H Br F Br OCH₂CF₃ i-Pr H Br F Br OCH₂CF₃ t-Bu H Br F Br OCH₂CF₃ Me Me Br F I CF₃ Me H Cl F I CF₃ Et H Cl F I CF₃ i-Pr H Cl F I CF₃ t-Bu H Cl F I CF₃ Me Me Cl F I CF₃ Me H Br F I CF₃ Et H Br F I CF₃ i-Pr H Br F I CF₃ t-Bu H Br F I CF₃ Me Me Br F I Cl Me H Cl F I Cl Et H Cl F I Cl i-Pr H Cl F I Cl t-Bu H Cl F I Cl Me Me Cl F I Cl Me H Br F I Cl Et H Br F I Cl i-Pr H Br F I Cl t-Bu H Br F I Cl Me Me Br F I Br Me H Cl F I Br Et H Cl F I Br i-Pr H Cl F I Br t-Bu H Cl F I Br Me Me Cl F I Br Me H Br F I Br Et H Br F I Br i-Pr H Br F I Br t-Bu H Br F I Br Me Me Br F I OCH₂CF₃ Me H Cl F I OCH₂CF₃ Et H Cl F I OCH₂CF₃ i-Pr H Cl F I OCH₂CF₃ t-Bu H Cl F I OCH₂CF₃ Me Me Cl F I OCH₂CF₃ Me H Br F I OCH₂CF₃ Et H Br F I OCH₂CF₃ i-Pr H Br F I OCH₂CF₃ t-Bu H Br F I OCH₂CF₃ Me Me Br F CF₃ CF₃ Me H Cl F CF₃ CF₃ Et H Cl F CF₃ CF₃ i-Pr H Cl F CF₃ CF₃ t-Bu H Cl F CF₃ CF₃ Me Me Cl F CF₃ CF₃ Me H Br F CF₃ CF₃ Et H Br F CF₃ CF₃ i-Pr H Br F CF₃ CF₃ t-Bu H Br F CF₃ CF₃ Me Me Br F CF₃ Cl Me H Cl F CF₃ Cl Et H Cl F CF₃ Cl i-Pr H Cl F CF₃ Cl t-Bu H Cl F CF₃ Cl Me Me Cl F CF₃ Cl Me H Br F CF₃ Cl Et H Br F CF₃ Cl i-Pr H Br F CF₃ Cl t-Bu H Br F CF₃ Cl Me Me Br F CF₃ Br Me H Cl F CF₃ Br Et H Cl F CF₃ Br i-Pr H Cl F CF₃ Br t-Bu H Cl F CF₃ Br Me Me Cl F CF₃ Br Me H Br F CF₃ Br Et H Br F CF₃ Br i-Pr H Br F CF₃ Br t-Bu H Br F CF₃ Br Me Me Br F CF₃ OCH₂CF₃ Me H Cl F CF₃ OCH₂CF₃ Et H Cl F CF₃ OCH₂CF₃ i-Pr H Cl F CF₃ OCH₂CF₃ t-Bu H Cl F CF₃ OCH₂CF₃ Me Me Cl F CF₃ OCH₂CF₃ Me H Br F CF₃ OCH₂CF₃ Et H Br F CF₃ OCH₂CF₃ i-Pr H Br F CF₃ OCH₂CF₃ t-Bu H Br F CF₃ OCH₂CF₃ Me Me Br CH₃ F OCHF₂ Me H Cl CH₃ F OCHF₂ Et H Cl CH₃ F OCHF₂ i-Pr H Cl CH₃ F OCHF₂ t-Bu H Cl CH₃ F OCHF₂ Me Me Cl CH₃ F OCHF₂ Me H Br CH₃ F OCHF₂ Et H Br CH₃ F OCHF₂ i-Pr H Br CH₃ F OCHF₂ t-Bu H Br CH₃ F OCHF₂ Me Me Br CH₃ Cl OCHF₂ Me H Cl CH₃ Cl OCHF₂ Et H Cl CH₃ Cl OCHF₂ i-Pr H Cl CH₃ Cl OCHF₂ t-Bu H Cl CH₃ Cl OCHF₂ Me Me Cl CH₃ Cl OCHF₂ Me H Br CH₃ Cl OCHF₂ Et H Br CH₃ Cl OCHF₂ i-Pr H Br CH₃ Cl OCHF₂ t-Bu H Br CH₃ Cl OCHF₂ Me Me Br CH₃ Br OCHF₂ Me H Cl CH₃ Br OCHF₂ Et H Cl CH₃ Br OCHF₂ i-Pr H Cl CH₃ Br OCHF₂ t-Bu H Cl CH₃ Br OCHF₂ Me Me Cl CH₃ Br OCHF₂ Me H Br CH₃ Br OCHF₂ Et H Br CH₃ Br OCHF₂ i-Pr H Br CH₃ Br OCHF₂ t-Bu H Br CH₃ Br OCHF₂ Me Me Br CH₃ I OCHF₂ Me H Cl CH₃ I OCHF₂ Et H Cl CH₃ I OCHF₂ i-Pr H Cl CH₃ I OCHF₂ t-Bu H Cl CH₃ I OCHF₂ Me Me Cl CH₃ I OCHF₂ Me H Br CH₃ I OCHF₂ Et H Br CH₃ I OCHF₂ i-Pr H Br CH₃ I OCHF₂ t-Bu H Br CH₃ I OCHF₂ Me Me Br CH₃ CF₃ OCHF₂ Me H Cl CH₃ CF₃ OCHF₂ Et H Cl CH₃ CF₃ OCHF₂ i-Pr H Cl CH₃ CF₃ OCHF₂ t-Bu H Cl CH₃ CF₃ QCHF2 Me Me Cl CH₃ CF₃ OCRF2 Me H Br CH₃ CF₃ OCHF₂ i-Pr H Br CH₃ CF₃ OCHF₂ t-Bu H Br CH₃ CF₃ OCHF₂ Me Me Br F F OCHF₂ Me H Cl F F OCHF₂ Et H Cl F F OCHF₂ i-Pr H Cl F F OCHF₂ t-Bu H Cl F F OCHF₂ Me Me Cl F F OCHF₂ Me H Br F F OCHF₂ Et H Br F F OCHF₂ i-Pr H Br F F OCHF₂ t-Bu H Br F F OCHF₂ Me Me Br F Cl OCHF₂ Me H Cl F Cl OCHF₂ Et H Cl F Cl OCHF₂ i-Pr H Cl F Cl OCHF₂ t-Bu H Cl F Cl OCHF₂ Me Me Cl F Cl OCHF₂ Me H Br F Cl OCHF₂ Et H Br F Cl OCHF₂ i-Pr H Br F Cl OCHF₂ t-Bu H Br F Cl OCHF₂ Me Me Br F Br OCHF₂ Me H Cl F Br OCHF₂ Et H Cl F Br OCHF₂ i-Pr H Cl F Br OCHF₂ t-Bu H Cl F Br OCHF₂ Me Me Cl F Br OCHF₂ Me H Br F Br OCHF₂ Et H Br F Br OCHF₂ i-Pr H Br F Br OCHF₂ t-Bu H Br F Br OCHF₂ Me Me Br F I OCHF₂ Me H Cl F I OCHF₂ Et H Cl F I OCHF₂ i-Pr H Cl F I OCHF₂ t-Bu H Cl F I OCHF₂ Me Me Cl F I OCHF₂ Me H Br F I OCHF₂ Et H Br F I OCHF₂ i-Pr H Br F I OCHF₂ t-Bu H Br F I OCHF₂ Me Me Br F CF₃ OCHF₂ Me H Cl F CF₃ OCHF₂ Et H Cl F CF₃ OCHF₂ i-Pr H Cl F CF₃ OCHF₂ t-Bu H Cl F CF₃ OCHF₂ Me Me Cl F CF₃ OCHF₂ Me H Br F CF₃ OCHF₂ Et H Br F CF₃ OCHF₂ i-Pr H Br F CF₃ OCHF₂ t-Bu H Br F CF₃ OCHF₂ Me Me Br CH₃ CN CF₃ Me H Cl CH₃ CN CF₃ Et H Cl CH₃ CN CF₃ i-Pr H Cl CH₃ CN CF₃ t-Bu H Cl CH₃ CN CF₃ Me Me Cl CH₃ CN CF₃ Me H Br CH₃ CN CF₃ Et H Br CH₃ CN CF₃ i-Pr H Br CH₃ CN CF₃ t-Bu H Br CH₃ CN CF₃ Me Me Br CH₃ CN Cl Me H Cl CH₃ CN Cl Et H Cl CH₃ CN Cl i-Pr H Cl CH₃ CN Cl t-Bu H Cl CH₃ CN Cl Me Me Cl CH₃ CN Cl Me H Br CH₃ CN Cl Et H Br CH₃ CN Cl i-Pr H Br CH₃ CN Cl t-Bu H Br CH₃ CN Cl Me Me Br CH₃ CN Br Me H Cl CH₃ CN Br Et H Cl CH₃ CN Br i-Pr H Cl CH₃ CN Br t-Bu H Cl CH₃ CN Br Me Me Cl CH₃ CN Br Me H Br CH₃ CN Br Et H Br CH₃ CN Br i-Pr H Br CH₃ CN Br t-Bu H Br CH₃ CN Br Me Me Br CH₃ CN OCH₂CF₃ Me H Cl CH₃ CN OCH₂CF₃ Et H Cl CH₃ CN OCH₂CF₃ i-Pr H Cl CH₃ CN OCH₂CF₃ t-Bu H Cl CH₃ CN OCH₂CF₃ Me Me Cl CH₃ CN OCH₂CF₃ Me H Br CH₃ CN OCH₂CF₃ Et H Br CH₃ CN OCH₂CF₃ i-Pr H Br CH₃ CN OCH₂CF₃ t-Bu H Br CH₃ CN OCH₂CF₃ Me Me Br F CN CF₃ Me H Cl F CN CF₃ Et H Cl F CN CF₃ i-Pr H Cl F CN CF₃ t-Bu H Cl F CN CF₃ Me Me Cl F CN CF₃ Me H Br F CN CF₃ Et H Br F CN CF₃ i-Pr H Br F CN CF₃ t-Bu H Br F CN CF₃ Me Me Br F CN Cl Me H Cl F CN Cl Et H Cl F CN Cl i-Pr H Cl F CN Cl t-Bu H Cl F CN Cl Me Me Cl F CN Cl Me H Br F CN Cl Et H Br F CN Cl i-Pr H Br F CN Cl t-Bu H Br F CN Cl Me Me Br F CN Br Me H Cl F CN Br Et H Cl F CN Br i-Pr H Cl F CN Br t-Bu H Cl F CN Br Me Me Cl F CN Br Me H Br F CN Br Et H Br F CN Br i-Pr H Br F CN Br t-Bu H Br F CN Br Me Me Br F CN OCH₂CF₃ Me H Cl F CN OCH₂CF₃ Et H Cl F CN OCH₂CF₃ i-Pr H Cl F CN OCH₂CF₃ t-Bu H Cl F CN OCH₂CF₃ Me Me Cl F CN OCH₂CF₃ Me H Br F CN OCH₂CF₃ Et H Br F CN OCH₂CF₃ i-Pr H Br F CN OCH₂CF₃ t-Bu H Br F CN OCH₂CF₃ Me Me Br CH₃ CN OCH₂CF₃ Me H Cl CH₃ CN OCHF₂ Et H Cl CH₃ CN OCHF₂ i-Pr H Cl CH₃ CN OCHF₂ t-Bu H Cl CH₃ CN OCHF₂ Me Me Cl CH₃ CN OCHF₂ Me H Br CH₃ CN OCHF₂ Et H Br CH₃ CN OCHF₂ i-Pr H Br CH₃ CN OCHF₂ t-Bu H Br CH₃ CN OCHF₂ Me Me Br F CN OCHF₂ Me H Cl F CN OCHF₂ Et H Cl F CN OCHF₂ i-Pr H Cl F CN OCHF₂ t-Bu H Cl F CN OCHF₂ Me Me Cl F CN OCHF₂ Me H Br F CN OCHF₂ Et H Br F CN OCHF₂ i-Pr H Br F CN OCHF₂ t-Bu H Br F CN OCHF₂ Me Me Br Cl F CF₃ Me H Cl Cl F CF₃ Et H Cl Cl F CF₃ i-Pr H Cl Cl F CF₃ t-Bu H Cl Cl F CF₃ Me Me Cl Cl F CF₃ Me H Br Cl F CF₃ Et H Br Cl F CF₃ i-Pr H Br Cl F CF₃ t-Bu H Br Cl F CF₃ Me Me Br Cl F Cl Me H Cl Cl F Cl Et H Cl Cl F Cl i-Pr H Cl Cl F Cl t-Bu H Cl Cl F Cl Me Me Cl Cl F Cl Me H Br Cl F Cl Et H Br Cl F Cl i-Pr H Br Cl F Cl t-Bu H Br Cl F Cl Me Me Br Cl F Br Me H Cl Cl F Br Et H Cl Cl F Br i-Pr H Cl Cl F Br t-Bu H Cl Cl F Br Me Me Cl Cl F Br Me H Br Cl F Br Et H Br Cl F Br i-Pr H Br Cl F Br t-Bu H Br Cl F Br Me Me Br Cl F OCH₂CF₃ Me H Cl Cl F OCH₂CF₃ Et H Cl Cl F OCH₂CF₃ i-Pr H Cl Cl F OCH₂CF₃ t-Bu H Cl Cl F OCH₂CF₃ Me Me Cl Cl F OCH₂CF₃ Me H Br Cl F OCH₂CF₃ Et H Br Cl F OCH₂CF₃ i-Pr H Br Cl F OCH₂CF₃ t-Bu H Br Cl F OCH₂CF₃ Me Me Br Cl Cl CF₃ Me H Cl Cl Cl CF₃ Et H Cl Cl Cl CF₃ i-Pr H Cl Cl Cl CF₃ t-Bu H Cl Cl Cl CF₃ Me Me Cl Cl Cl CF₃ Me H Br Cl Cl CF₃ Et H Br Cl Cl CF₃ i-Pr H Br Cl Cl CF₃ t-Bu H Br Cl Cl CF₃ Me Me Br Cl Cl Cl Me H Cl Cl Cl Cl Et H Cl Cl Cl Cl i-Pr H Cl Cl Cl Cl t-Bu H Cl Cl Cl Cl Me Me Cl Cl Cl Cl Me H Br Cl Cl Cl Et H Br Cl Cl Cl i-Pr H Br Cl Cl Cl t-Bu H Br Cl Cl Cl Me Me Br Cl Cl Br Me H Cl Cl Cl Br Et H Cl Cl Cl Br i-Pr H Cl Cl Cl Br t-Bu H Cl Cl Cl Br Me Me Cl Cl Cl Br Me H Br Cl Cl Br Et H Br Cl Cl Br i-Pr H Br Cl Cl Br t-Bu H Br Cl Cl Br Me Me Br Cl Cl OCH₂CF₃ Me H Cl Cl Cl OCH₂CF₃ Et H Cl Cl Cl OCH₂CF₃ i-Pr H Cl Cl Cl OCH₂CF₃ t-Bu H Ci Cl Cl OCH₂CF₃ Me Me Cl Cl Cl OCH₂CF₃ Me H Br Cl Cl OCH₂CF₃ Et H Br Cl Cl OCH₂CF₃ i-Pr H Br Cl Cl OCH₂CF₃ t-Bu H Br Cl Cl OCH₂CF₃ Me Me Br Cl Br CF₃ Me H Cl Cl Br CF₃ Et H Cl Cl Br CF₃ i-Pr H Cl Cl Br CF₃ t-Bu H Cl Cl Br CF₃ Me Me Cl Cl Br CF₃ Me H Br Cl Br CF₃ Et H Br Cl Br CF₃ i-Pr H Br Cl Br CF₃ t-Bu H Br Cl Br CF₃ Me Me Br Cl Br Cl Me H Cl Cl Br Cl Et H Cl Cl Br Cl i-Pr H Cl Cl Br Cl t-Bu H Cl Cl Br Cl Me Me Cl Cl Br Cl Me H Br Cl Br Cl Et H Br Cl Br Cl i-Pr H Br Cl Br Cl t-Bu H Br Cl Br Cl Me Me Br Cl Br Br Me H Cl Cl Br Br Et H Cl Cl Br Br i-Pr H Cl Cl Br Br t-Bu H Cl Cl Br Br Me Me Cl Cl Br Br Me H Br Cl Br Br Et H Br Cl Br Br i-Pr H Br Cl Br Br t-Bu H Br Cl Br Br Me Me Br Cl Br OCH₂CF₃ Me H Cl Cl Br OCH₂CF₃ Et H Cl Cl Br OCH₂CF₃ i-Pr H Cl Cl Br OCH₂CF₃ t-Bu H Cl Cl Br OCH₂CF₃ Me Me Cl Cl Br OCH₂CF₃ Me H Br Cl Br OCH₂CF₃ Et H Br Cl Br OCH₂CF₃ i-Pr H Br Cl Br OCH₂CF₃ t-Bu H Br Cl Br OCH₂CF₃ Me Me Br Cl I CF₃ Me H Cl Cl I CF₃ Et H Cl Cl I CF₃ i-Pr H Cl Cl I CF₃ t-Bu H Cl Cl I CF₃ Me Me Cl Cl I CF₃ Me H Br Cl I CF₃ Et H Br Cl I CF₃ i-Pr H Br Cl I CF₃ t-Bu H Br Cl I CF₃ Me Me Br Cl I Cl Me H Cl Cl I Cl Et H Cl Cl I Cl i-Pr H Cl Cl I Cl t-Bu H Cl Cl I Cl Me Me Cl Cl I Cl Me H Br Cl I Cl Et H Br Cl I Cl i-Pr H Br Cl I Cl t-Bu H Br Cl I Cl Me Me Br Cl I Br Me H Cl Cl I Br Et H Cl Cl I Br i-Pr H Cl Cl I Br t-Bu H Cl Cl I Br Me Me Cl Cl I Br Me H Br Cl I Br Et H Br Cl I Br i-Pr H Br Cl I Br t-Bu H Br Cl I Br Me Me Br Cl I OCH₂CF₃ Me H Cl Cl I OCH₂CF₃ Et H Cl Cl I OCH₂CF₃ i-Pr H Cl Cl I OCH₂CF₃ t-Bu H Cl Cl I OCH₂CF₃ Me Me Cl Cl I OCH₂CF₃ Me H Br Cl I OCH₂CF₃ Et H Br Cl I OCH₂CF₃ i-Pr H Br Cl I OCH₂CF₃ t-Bu H Br Cl I OCH₂CF₃ Me Me Br Cl CF₃ CF₃ Me H Cl Cl CF₃ CF₃ Et H Cl Cl CF₃ CF₃ i-Pr H Cl Cl CF₃ CF₃ t-Bu H Cl Cl CF₃ CF₃ Me Me Cl Cl CF₃ CF₃ Me H Br Cl CF₃ CF₃ Et H Br Cl CF₃ CF₃ i-Pr H Br Cl CF₃ CF₃ t-Bu H Br Cl CF₃ CF₃ Me Me Br Cl CF₃ Cl Me H Cl Cl CF₃ Cl Et H Cl Cl CF₃ Cl i-Pr H Cl Cl CF₃ Cl t-Bu H Cl Cl CF₃ Cl Me Me Cl Cl CF₃ Cl Me H Br Cl CF₃ Cl Et H Br Cl CF₃ Cl i-Pr H Br Cl CF₃ Cl t-Bu H Br Cl CF₃ Cl Me Me Br Cl CF₃ Br Me H Cl Cl CF₃ Br Et H Cl Cl CF₃ Br i-Pr H Cl Cl CF₃ Br t-Bu H Cl Cl CF₃ Br Me Me Cl Cl CF₃ Br Me H Br Cl CF₃ Br Et H Br Cl CF₃ Br i-Pr H Br Cl CF₃ Br t-Bu H Br Cl CF₃ Br Me Me Br Cl CF₃ OCH₂CF₃ Me H Cl Cl CF₃ OCH₂CF₃ Et H Cl Cl CF₃ OCH₂CF₃ i-Pr H Cl Cl CF₃ OCH₂CF₃ t-Bu H Cl Cl CF₃ OCH₂CF₃ Me Me Cl Cl CF₃ OCH₂CF₃ Me H Br Cl CF₃ OCH₂CF₃ Et H Br Cl CF₃ OCH₂CF₃ i-Pr H Br Cl CF₃ OCH₂CF₃ t-Bu H Br Cl CF₃ OCH₂CF₃ Me Me Br Cl Cl Cl n-Pr H Cl Cl Cl Cl n-Bu H Cl Cl Cl Cl s-Bu H Cl Cl Cl Cl i-Bu H Cl Cl Cl Cl Et Me Cl Br F CF₃ Me H Cl Br F CF₃ Et H Cl Br F CF₃ i-Pr H Cl Br F CF₃ t-Bu H Cl Br F CF₃ Me Me Cl Br F CF₃ Me H Br Br F CF₃ Et H Br Br F CF₃ i-Pr H Br Br F CF₃ t-Bu H Br Br F CF₃ Me Me Br Br F Cl Me H Cl Br F Cl Et H Cl Br F Cl i-Pr H Cl Br F Cl t-Bu H Cl Br F Cl Me Me Cl Br F Cl Me H Br Br F Cl Et H Br Br F Cl i-Pr H Br Br F Cl t-Bu H Br Br F Cl Me Me Br Br F Br Me H Cl Br F Br Et H Cl Br F Br i-Pr H Cl Br F Br t-Bu H Cl Br F Br Me Me Cl Br F Br Me H Br Br F Br Et H Br Br F Br i-Pr H Br Br F Br t-Bu H Br Br F Br Me Me Br Br F OCH₂CF₃ Me H Cl Br F OCH₂CF₃ Et H Cl Br F OCH₂CF₃ i-Pr H Cl Br F OCH₂CF₃ t-Bu H Cl Br F OcH2CF₃ Me Me Cl Br F OCH₂CF₃ Me H Br Br F OCH₂CF₃ Et H Br Br F OCH₂CF₃ i-Pr H Br Br F OCH₂CF₃ t-Bu H Br Br F OCH₂CF₃ Me Me Br Br Cl CF₃ Me H Cl Br Cl CF₃ Et H Cl Br Cl CF₃ i-Pr H Cl Br Cl CF₃ t-Bu H Cl Br Cl CF₃ Me Me Cl Br Cl CF₃ Me H Br Br Cl CF₃ Et H Br Br Cl CF₃ i-Pr H Br Br Cl CF₃ t-Bu H Br Br Cl CF₃ Me Me Br Br Cl Cl Me H Cl Br Cl Cl Et H Cl Br Cl Cl i-Pr H Cl Br Cl Cl t-Bu H Cl Br Cl Cl Me Me Cl Br Cl Cl Me H Br Br Cl Cl Et H Br Br Cl Cl i-Pr H Br Br Cl Cl t-Bu H Br Br Cl Cl Me Me Br Br Cl Br Me H Cl Br Cl Br Et H Cl Br Cl Br i-Pr H Cl Br Cl Br t-Bu H Cl Br Cl Br Me Me Cl Br Cl Br Me H Br Br Cl Br Et H Br Br Cl Br i-Pr H Br Br Cl Br t-Bu H Br Br Cl Br Me Me Br Br Cl OCH₂CF₃ Me H Cl Br Cl OCH₂CF₃ Et H Cl Br Cl OCH₂CF₃ i-Pr H Cl Br Cl OCH₂CF₃ t-Bu H Cl Br Cl OCH₂CF₃ Me Me Cl Br Cl OCH₂CF₃ Me H Br Br Cl OCH₂CF₃ Et H Br Br Cl OCH₂CF₃ i-Pr H Br Br Cl OCH₂CF₃ t-Bu H Br Br Cl OCH₂CF₃ Me Me Br Br Br CF₃ Me H Cl Br Br CF₃ Et H Cl Br Br CF₃ i-Pr H Cl Br Br CF₃ t-Bu H Cl Br Br CF₃ Me Me Cl Br Br CF₃ Me H Br Br Br CF₃ Et H Br Br Br CF₃ i-Pr H Br Br Br CF₃ t-Bu H Br Br Br CF₃ Me Me Br Br Br Cl Me H Cl Br Br Cl Et H Cl Br Br Cl i-Pr H Cl Br Br Cl t-Bu H Cl Br Br Cl Me Me Cl Br Br Cl Me H Br Br Br Cl Et H Br Br Br Cl i-Pr H Br Br Br Cl t-Bu H Br Br Br Cl Me Me Br Br Br Br Me H Cl Br Br Br Et H Cl Br Br Br i-Pr H Cl Br Br Br t-Bu H Cl Br Br Br Me Me Cl Br Br Br Me H Br Br Br Br Et H Br Br Br Br i-Pr H Br Br Br Br t-Bu H Br Br Br Br Me Me Br Br Br OCH₂CF₃ Me H Cl Br Br OCH₂CF₃ Et H Cl Br Br OCH₂CF₃ i-Pr H Cl Br Br OCH₂CF₃ t-Bu H Cl Br Br OCH₂CF₃ Me Me Cl Br Br OCH₂CF₃ Me H Br Br Br OCH₂CF₃ Et H Br Br Br OCH₂CF₃ i-Pr H Br Br Br OCH₂CF₃ t-Bu H Br Br Br OCH₂CF₃ Me Me Br Br I CF₃ Me H Cl Br I CF₃ Et H Cl Br I CF₃ i-Pr H Cl Br I CF₃ t-Bu H Cl Br I CF₃ Me Me Cl Br I CF₃ Me H Br Br I CF₃ Et H Br Br I CF₃ i-Pr H Br Br I CF₃ t-Bu H Br Br I CF₃ Me Me Br Br I Cl Me H Cl Br I Cl Et H Cl Br I Cl i-Pr H Cl Br I Cl t-Bu H Cl Br I Cl Me Me Cl Br I Cl Me H Br Br I Cl Et H Br Br I Cl i-Pr H Br Br I Cl t-Bu H Br Br I Cl Me Me Br Br I Br Me H Cl Br I Br Et H Cl Br I Br i-Pr H Cl Br I Br t-Bu H Cl Br I Br Me Me Cl Br I Br Me H Br Br I Br Et H Br Br I Br i-Pr H Br Br I Br t-Bu H Br Br I Br Me Me Br Br I OCH₂CF₃ Me H Cl Br I OCH₂CF₃ Et H Cl Br I OCH₂CF₃ i-Pr H Cl Br I OCH₂CF₃ t-Bu H Cl Br I OCH₂CF₃ Me Me Cl Br I OCH₂CF₃ Me H Br Br I OCH₂CF₃ Et H Br Br I OCH₂CF₃ i-Pr H Br Br I OCH₂CF₃ t-Bu H Br Br I OCH₂CF₃ Me Me Br Br CF₃ CF₃ Me H Cl Br CF₃ CF₃ Et H Cl Br CF₃ CF₃ i-Pr H Cl Br CF₃ CF₃ t-Bu H Cl Br CF₃ CF₃ Me Me Cl Br CF₃ CF₃ Me H Br Br CF₃ CF₃ Et H Br Br CF₃ CF₃ i-Pr H Br Br CF₃ CF₃ t-Bu H Br Br CF₃ CF₃ Me Me Br Br CF₃ Cl Me H Cl Br CF₃ Cl Et H Cl Br CF₃ Cl i-Pr H Cl Br CF₃ Cl t-Bu H Cl Br CF₃ Cl Me Me Cl Br CF₃ Cl Me H Br Br CF₃ Cl Et H Br Br CF₃ Cl i-Pr H Br Br CF₃ Cl t-Bu H Br Br CF₃ Cl Me Me Br Br CF₃ Br Me H Cl Br CF₃ Br Et H Cl Br CF₃ Br i-Pr H Cl Br CF₃ Br t-Bu H Cl Br CF₃ Br Me Me Cl Br CF₃ Br Me H Br Br CF₃ Br Et H Br Br CF₃ Br i-Pr H Br Br CF₃ Br t-N H Br Br CF₃ Br Me Me Br Br CF₃ OCH₂CF₃ Me H Cl Br CF₃ OCH₂CF₃ Et H Cl Br CF₃ OCH₂CF₃ i-Pr H Cl Br CF₃ OCH₂CF₃ t-Bu H Cl Br CF₃ OCH₂CF₃ Me Me Cl Br CF₃ OCH₂CF₃ Me H Br Br CF₃ OCH₂CF₃ Et H Br Br CF₃ OCH₂CF₃ i-Pr H Br Br CF₃ OCH₂CF₃ t-Bu H Br Br CF₃ OCH₂CF₃ Me Me Br Cl F OCHF₂ Me H Cl Cl F OCHF₂ Et H Cl Cl F OCHF₂ i-Pr H Cl Cl F OCHF₂ t-Bu H Cl Cl F OCHF₂ Me Me Cl Cl F OCHF₂ Me H Br Cl F OCHP2 Et H Br Cl F OCHF₂ i-Pr H Br Cl F OCHF₂ t-Bu H Br Cl F OCHF₂ Me Me Br Cl Cl OCHF₂ Me H Cl Cl Cl OCHF₂ Et H Cl Cl Cl OCHF₂ t-Pr H Cl Cl Cl OCHF₂ t-Bu H Cl Cl Cl OCHF₂ Me Me Cl Cl Cl OCHF₂ Me H Br Cl Cl OCHF₂ Et H Br Cl Cl OCHF₂ i-Pr H Br Cl Cl OCHF₂ t-Bu H Br Cl Cl OCHF₂ Me Me Br Cl Br OCHF₂ Me H Cl Cl Br OCHF₂ Et H Cl Cl Br OCHF₂ i-Pr H Cl Cl Br OCHF₂ t-Bu H Cl Cl Br OCHF₂ Me Me Cl Cl Br OCHF₂ Me H Br Cl Br OCHF₂ Et H Br Cl Br OCHF₂ i-Pr H Br Cl Br OCHF₂ t-Bu H Br Cl Br OCHF₂ Me Me Br Cl I OCHF₂ Me H Cl Cl I OCHF₂ Et H Cl Cl I OCHF₂ i-Pr H Cl Cl I OCHF₂ t-Bu H Cl Cl I OCHF₂ Me Me Cl Cl I OCHF₂ Me H Br Cl I OCHF₂ Et H Br Cl I OCHF₂ i-Pr H Br Cl I OCHF₂ t-Bu H Br Cl I OCHF₂ Me Me Br Cl CF₃ OCHF₂ Me H Cl Cl CF₃ OCHF₂ Et H Cl Cl CF₃ OCHF₂ i-Pr H Cl Cl CF₃ OCHF₂ t-Bu H Cl Cl CF₃ OCHF₂ Me Me Cl Cl CF₃ OCHF₂ Me H Br Cl CF₃ OCHF₂ Et H Br Cl CF₃ OCHF₂ i-Pr H Br Cl CF₃ OCHF₂ t-Bu H Br Cl CF₃ OCHF₂ Me Me Br Br F OCHF₂ Me H Cl Br F OCHF₂ Et H Cl Br F OCHF₂ i-Pr H Cl Br F OCHF₂ t-Bu H Cl Br F OCHF₂ Me Me Cl Br F OCHF₂ Me H Br Br F OCHF₂ Et H Br Br F OCHF₂ i-Pr H Br Br F OCHF₂ t-Bu H Br Br F OCHF₂ Me Me Br Br Cl OCHF₂ Me H Cl Br Cl OCHF₂ Et H Cl Br Cl OCHF₂ i-Pr H Cl Br Cl OCHF₂ t-Bu H Cl Br Cl OCHF₂ Me Me Cl Br Cl OCHF₂ Me H Br Br Cl OCHF₂ Et H Br Br Cl OCHF₂ i-Pr H Br Br Cl OCHF₂ t-Bu H Br Br Cl OCHF₂ Me Me Br Br Br OCHF₂ Me H Cl Br Br OCHF₂ Et H Cl Br Br OCHF₂ i-Pr H Cl Br Br OCHF₂ t-Bu H Cl Br Br OCHF₂ Me Me Cl Br Br OCHF₂ Me H Br Br Br OCHF₂ Et H Br Br Br OCHF₂ i-Pr H Br Br Br OCHF₂ t-Bu H Br Br Br OCHF₂ Me Me Br Br I OCHF₂ Me H Cl Br I OCHF₂ Et H Cl Br I OCHF₂ i-Pr H Cl Br I OCHF₂ t-Bu H Cl Br I OCHF₂ Me Me Cl Br I OCHF₂ Me H Br Br I OCHF₂ Et H Br Br I OCHF₂ i-Pr H Br Br I OCHF₂ t-Bu H Br Br I OCHF₂ Me Me Br Br CF₃ OCHF₂ Me H Cl Br CF₃ OCHF₂ Et H Cl Br CF₃ OCHF₂ i-Pr H Cl Br CF₃ OCHF₂ t-Bu H Cl Br CF₃ OCHF₂ Me Me Cl Br CF₃ OCHF₂ Me H Br Br CF₃ OCHF₂ Et H Br Br CF₃ OCHF₂ i-Pr H Br Br CF₃ OCHF₂ t-Bu H Br Br CF₃ OCHF₂ Me Me Br Cl CN CF₃ Me H Cl Cl CN CF₃ Et H Cl Cl CN CF₃ i-Pr H Cl Cl CN CF₃ t-Bu H Cl Cl CN CF₃ Me Me Cl Cl CN CF₃ Me H Br Cl CN CF₃ Et H Br Cl CN CF₃ i-Pr H Br Cl CN CF₃ t-Bu H Br Cl CN CF₃ Me Me Br Cl CN Cl Me H Cl Cl CN Cl Et H Cl Cl CN Cl i-Pr H Cl Cl CN Cl t-Bu H Cl Cl CN Cl Me Me Cl Cl CN Cl Me H Br Cl CN Cl Et H Br Cl CN Cl i-Pr H Br Cl CN Cl t-Bu H Br Cl CN Cl Me Me Br Cl CN Br Me H Cl Cl CN Br Et H Cl Cl CN Br i-Pr H Cl Cl CN Br t-Bu H Cl Cl CN Br Me Me Cl Cl CN Br Me H Br Cl CN Br Et H Br Cl CN Br i-Pr H Br Cl CN Br t-Bu H Br Cl CN Br Me Me Br Cl CN OCH₂CF₃ Me H Cl Cl CN OCH₂CF₃ Et H Cl Cl CN OCH₂CF₃ i-Pr H Cl Cl CN OCH₂CF₃ t-Bu H Cl Cl CN OCH₂CF₃ Me Me Cl Cl CN OCH₂CF₃ Me H Br Cl CN OCH₂CF₃ Et H Br Cl CN OCH₂CF₃ i-Pr H Br Cl CN OCH₂CF₃ t-Bu H Br Cl CN OCH₂CF₃ Me Me Br Br CN CF₃ Me H Cl Br CN CF₃ Et H Cl Br CN CF₃ i-Pr H Cl Br CN CF₃ t-Bu H Cl Br CN CF₃ Me Me Cl Br CN CF₃ Me H Br Br CN CF₃ Et H Br Br CN CF₃ i-Pr H Br Br CN CF₃ t-Bu H Br Br CN CF₃ Me Me Br Br CN Cl Me H Cl Br CN Cl Et H Cl Br CN Cl i-Pr H Cl Br CN Cl t-Bu H Cl Br CN Cl Me Me Cl Br CN Cl Me H Br Br CN Cl Et H Br Br CN Cl i-Pr H Br Br CN Cl t-Bu H Br Br CN Cl Me Me Br Br CN Br Me H Cl Br CN Br Et H Cl Br CN Br i-Pr H Cl Br CN Br t-Bu H Cl Br CN Br Me Me Cl Br CN Br Me H Br Br CN Br Et H Br Br CN Br i-Pr H Br Br CN Br t-Bu H Br Br CN Br Me Me Br Br CN OCH₂CF₃ Me H Cl Br CN OCH₂CF₃ Et H Cl Br CN OCH₂CF₃ i-Pr H Cl Br CN OCH₂CF₃ t-Bu H Cl Br CN OCH₂CF₃ Me Me Cl Br CN OCH₂CF₃ Me H Br Br CN OCH₂CF₃ Et H Br Br CN OCH₂CF₃ i-Pr H Br Br CN OCH₂CF₃ t-Bu H Br Br CN OCH₂CF₃ Me Me Br Cl CN OCHF₂ Me H Cl Cl CN OCHF₂ Et H Cl Cl CN OCHF₂ i-Pr H Cl Cl CN OCHF₂ t-Bu H Cl Cl CN OCHF₂ Me Me Cl Cl CN OCHF₂ Me H Br Cl CN OCHF₂ Et H Br Cl CN OCHF₂ i-Pr H Br Cl CN OCHF₂ t-Bu H Br Cl CN OCHF₂ Me Me Br Br CN OCHF₂ Me H Cl Br CN OCHF₂ Et H Cl Br CN OCHF₂ i-Pr H Cl Br CN OCHF₂ t-Bu H Cl Br CN OCHF₂ Me Me Cl Br CN OCHF₂ Me H Br Br CN OCHF₂ Et H Br Br CN OCHF₂ i-Pr H Br Br CN OCHF₂ t-Bu H Br Br CN OCHF₂ Me Me Br 

1. A method for preparing a benzo[1,3]oxazinone, comprising: contacting a pyrrole or pyrazole carboxylic acid with a sulfonyl chloride and an isatoic anhydride in the presence of a tertiary amine to form the benzo[1,3]oxazinone, the nominal mole ratio of said sulfonyl chloride to said carboxylic acid being from about 1.0 to 1.5 and the nominal mole ratio of said isatoic anhydride to said carboxylic acid is from about 0.8 to 1.2.
 2. The method of claim 1 wherein the benzo[1,3]oxazinone is a compound of Formula 1

wherein J is an optionally substituted pyrrole or pyrazole; and K is, together with the two contiguous linking carbon atoms, a fused phenyl ring optionally substituted; the carboxylic acid is a compound of Formula 2 J-CO₂H  2  wherein J is defined as in Formula 1; the sulfonyl chloride is a compound of Formula 4 LS(O)₂Cl  4  wherein L is selected from alkyl, haloalkyl, and phenyl optionally substituted with from one to three substituents independently selected from alkyl or halogen; and the isatoic anhydride is a compound of Formula 5

 wherein K is defined as in Formula
 1. 3. The method of claim 2 wherein the nominal mole ratio of the isatoic anhydride to carboxylic acid is from about 0.9 to 1.1.
 4. The method of claim 3 wherein the nominal mole ratio of the tertiary amine to carboxylic acid is from about 2.0 to 4.0.
 5. The method of claim 2 wherein K is, together with the two contiguous linking carbon atoms, a fused phenyl ring optionally substituted with from one to four substituents independently selected from G, U, W or or R¹³; J is a pyrrole or pyrazole, each optionally substituted with from one to two substituents independently selected from G, U, W or R¹³; each G is a 5- or 6-membered nonaromatic heterocyclic ring optionally including one or two ring members selected from the group consisting of C(═O), SO or S(O)₂, each optionally substituted with from one to four substituents independently selected from W; each U is a phenyl ring, a benzyl group, a beazoyl group, a 5- or 6-membered heteroaromnatic ring, an aromatic 8-, 9- or 10-membered fused carbobicyclic ring system, an aromatic 8-, 9- or 10-membered fused heterobicyclic ring system, each optionally substituted with from one to four substituents independently selected from W; each W is independently C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl, C₂-C₄ haloalkenyl, C₃-C₆ halocycloalkyl, halogen, CN, NO_(2, C) ₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkcylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆ cycloalkylamino, (C₁-C₄ alkyl)(C₃-C₆ cycloalkyl)amino or C₃-C₆ trialkylsilyl; each R¹³ is B(OR¹⁷)₂; NH₂; SH; thiocyanato; C₃-C₈ trialkylsilyloxy; C₁-C₄ alkyldisulfide; SF₅; R¹⁹C(=E)-; R¹⁹C(=E)M-; R¹⁹MC(=E)-; (R¹⁹)MC(=E)M-; —OP(=Q)(OR¹⁹)₂; —S(O)₂MR¹⁹; R¹⁹S(O)₂M-; each E is independently O, S, NR¹⁵, NOR¹⁵, NN(R¹⁵)₂, N—S═O, N—ON or N—NO₂; each M is independently O, NR¹⁸ or S; Q is O or S; each R¹⁵ and each R¹⁹ is independently H; C₁-C₆ alkyl optionally substituted with one or more substituents selected from the group consisting of CN, NO₂, hydroxy, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ haloalkylthio, C₁-C₄ haloalkylsulfinyl, C₁-C₄ haloalkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, CO₂H, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylcarbonyl, C₃-C₆ trialkylsilyl, and a phenyl ring optionally substituted with one to three substituents independently selected from W; C₁-C₆ haloalkyl; C₃-C₆ cycloalkyl; or a phenyl ring optionally substituted with from one to three substituents independently selected from W; each R¹⁷ is independently H or C₁-C₄ alkyl; or B(OR¹⁷)₂ can form a ring wherein the two oxygen atoms are linked by a chain of two to three carbons optionally substituted with one or two substituents independently selected from methyl or C₂-C₆ alkoxycarbonyl; and each R¹⁸ is independently H, C₁-C₆ alkyl or C₁-C₆ haloalkyl.
 6. The method of claim 5 wherein K is, together with the two contiguous linking carbon atoms, a fused phenyl ring optionally substituted with from one to four substituents independently selected from W or R¹³.
 7. The method of claim 2 wherein the compound of Formula 1 is a compound of Formula 1a

wherein X is N or CR⁶; Y is N or CH; R⁴ is C₁-C₄ alkyl or halogen; R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, CN or halogen; R⁶ and R⁷ are independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, halogen, CN or C₁-C₄ haloalkoxy; R⁸ is H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl, C₂-C₄ haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆ cycloalkylamino, (C₁-C₄ alkyl)(C₃-C₆ cycloalkyl)amino, C₂-C₄ alkylcarbonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl, C₃-C₈ dialkylaminocarbonyl or C₃-C₆ trialkylsilyl; R⁹ is CF₃, OCF₃, OCHF₂, OCH₂CF₃, S(O)_(p)CF₃, S(O)_(p)CHF₂ or halogen; and p is 0, 1 or 2;  the compound of Formula 2 is a compound of Formula 2′ and the compound of Formula 5 is a compound of Formula 5′

 wherein the definitions of X, Y, R⁴, R⁵, R⁷, R⁸ and R⁹ are the same as for Formula 1a.
 8. The method of claim 7 wherein X is N; Y is N; R⁴ is CH₃, F, Cl or Br; R₅ is CF₃, CN, F, Cl, Br or I; R⁷ is Cl or Br; R⁸ is H; and R⁹ is CF₃, OCHF₂, OCH₂CF₃, Cl or Br. 